The Fluoroquinolone Toxicity Research Foundation

 
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 05-13-2003

www.fqresearch.org



To the Members of Congress

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 1939. 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 are not dose dependant and do NOT resolve upon cessation of therapy. In most cases such adverse drug reactions do not even manifest until weeks, months and even years after such therapy has been terminated. They also do NOT resolve and become chronic conditions to which there is no known treatment protocol. Tens of thousands (literally) of patients 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.

A review of the med watch database (November 1997- November 2001) indicates that the FDA has received no less than 32,000 adverse drug reaction reports with 774 associated fatalities involving Cipro, Floxin and Levaquin. It has been over two years since I had requested the data associated with the other fluoroquinolones under the Freedom of Information Act, and I have yet to receive this information. One must keep in mind that the date found within the med watch data base 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:

November 1997 – November 2001 (four years)

Drug ADR rate Fatality

Cipro 12,444 328

Floxin 7,255 173

Levaquin 11,656 273

The other fluoroquinolones are not included, as the FDA as of has not provided such information to me yet, despite the fact that it was requested over two years ago.

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". 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 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 continues to approve additional agents and monographs devoid of this caveat. 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. 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.

The warnings within the monographs for this class of chemotherapeutic agents minimizes, trivializes, and distorts the potential risk involved in such therapy and claim that such events resolve upon cessation of therapy. The FDA knows full well that they do not but allows such bold face lies to be printed on a daily basis and does nothing. Refusing to educate the physician and his or her patients. The following is a partial list of the adverse drug reactions, known, published and listed within the monographs for fluoroquinolones. You would need a Greek translator to readily identify these disease states within the monographs for in a blatant effort to confuse the physician and the patient common verbiage is substituted with arcane medical terms and descriptions.

CARDIOVASCULAR

SUMMARY

QT prolongation and polymorphic ventricular tachycardia have been reported with therapeutic use.

CLINICAL EFFECTS

A. THROMBOPHLEBITIS

1. Thrombophlebitis and phlebitis were the most frequently reported adverse effect from parenteral administration of ciprofloxacin (Rahm & Schacht, 1989).

B. QT INCREASED

1. SUMMARY - QT prolongation has occurred following the therapeutic use of several fluoroquinolones, which have included grepafloxacin, levofloxacin, and sparfloxacin.

2. GREPAFLOXACIN -

a. WITHDRAWAL FROM MARKET - Grepafloxacin was withdrawn from the worldwide market in October 1999 after reports of cardiovascular toxicity; QT prolongation had been associated with its use (Sweetman, 2000).

b. During a phase I study, QTc prolongation was observed in healthy volunteers (Prod Info Raxar(R), 1997; Stahlmann & Lode, 1999).

3. LEVOFLOXACIN - QTc interval prolongation and polymorphic ventricular tachycardia were associated with the use of levofloxacin in an 88-year-old female hospitalized with atrial fibrillation, bronchitis, and mild congestive heart failure (Samaha, 1999). Despite the patient's underlying medical condition, the author noted that the patient continued to have a prolonged QTc interval until levofloxacin was discontinued.

a. In postmarketing experience, the development of torsades de pointes is extremely rare, and generally has occurred in patients with significant co-morbidities (Kahn, 2000).

4. GATIFLOXACIN/LACK OF EFFECT - In a small study (n=40) of healthy male volunteers, alterations in QT interval were NOT considered to be clinically relevant following the use of gatifloxacin at doses up to 800 milligrams (Gajjar et al, 2000).

5. SPARFLOXACIN - In European trials, QTc prolongation by a mean of 10 msec was reported with sparfloxacin use, but NO clinically significant arrhythmias developed (Lipsky & Baker, 1999).

NEUROLOGIC

SUMMARY


A. Headache, dizziness, and drowsiness have all been reported when used therapeutically and in overdose.

B. At therapeutic doses seizures, hallucinations, and sleep disturbances have been reported.

CLINICAL EFFECTS

A. SEIZURES


1. SUMMARY

a. Seizure activity has been reported with the therapeutic use of most fluoroquinolones.

2. CASE SERIES

a. CIPROFLOXACIN -

(1) Grand mal epileptic seizures have been reported in 3 cases after receiving CIPROFLOXACIN. However, 2 of the patients had a history of brain disorder prior to ciprofloxacin treatment.

(2) It has not been clearly established that the seizures and ciprofloxacin are related (Slavich et al, 1989; Arcieri et al, 1989).

b. NORFLOXACIN -

(1) There are 7 cases reported of seizures in patients receiving NORFLOXACIN. It has been suggested that 4 of the cases possessed factors that may have predisposed them to seizures and norfloxacin may have lowered their seizure threshold.

(2) A clear relationship between norfloxacin and seizures has not been established (Anon, 1990; Anastasio et al, 1988).

c. OFLOXACIN -

(1) There are several cases of seizures resulting from the therapeutic administration of OFLOXACIN. Severe renal dysfunction, underlying CNS pathology and a past history of epilepsy were thought to be predisposing factors (Sawada et al, 1991; Walton et al, 1998).

d. TROVAFLOXACIN -

(1) Seizure activity was reported in an adult within the first 12 hours of intravenous therapy with trovafloxacin (Menzies et al, 1999).

B. CNS EFFECTS

1. SUMMARY - Headache, nervousness, anxiety, lightheadedness, and dizziness have been observed during therapeutic use of these agents (Boerema et al, 1985; Holmes et al, 1985; Ball, 1989; Rahm & Schacht, 1989; Prod Info Raxar(R), 1997; Prod Info Trovan(R), 1997; Gajjar et al, 2000).

C. DREAMING ABNORMAL

1. Sleep disturbances and nightmares were reported in one of the clinical trials of FLEROXACIN, a trifluorinated quinolone with a long half-life. The sleep disturbances and nightmares were severe and traumatic enough to result in several of the patients' inability to work (Bowie et al, 1989).

D. PARESTHESIA

1. CIPROFLOXACIN - Paresthesias have been associated with the therapeutic use of CIPROFLOXACIN (Rahm & Schacht, 1989).

E. CEREBELLAR SYNDROME

1. SPECIFIC SUBSTANCE -

a. OFLOXACIN - An overdose of 3 grams of ofloxacin in an adult produced dizziness, drowsiness, disorientation, and slurred speech (Kohler et al, 1991).

b. PEFLOXACIN - Cerebellar dysfunction and an extrapyramidal syndrome, characterized by confusion, irregular asymmetrical involuntary movements, and slurred speech have been reported after therapeutic use of PEFLOXACIN (Lucet et al, 1988).

F. DYSKINESIA

1. CASE REPORTS

a. CIPROFLOXACIN -

(1) A 90-year-old male developed "whole body tremors and facial spasms" three days after starting ciprofloxacin 500 mg twice daily (Burkhart et al, 2000). Orofacial dyskinesia with truncal and extremity myoclonus was observed during neurological exam. Symptoms resolved completely within 24 hours of drug cessation.

b. TROVAFLOXACIN -

(1) Unsteady gait, dizziness and mental confusion were reported in an adult female following 7 days of oral trovafloxacin (200 mg daily) therapy; symptoms resolved gradually over a 2 week period after discontinuation of therapy (Menzies et al, 1999).

G. TREMOR

1. CASE REPORTS

a. CIPROFLOXACIN - A 16-year-old male developed tremor in both hands lasting 4 hours after ingesting 12 grams of ciprofloxacin (Cohen & Franciseo, 1994).

b. TROVAFLOXACIN - An 86-year-old female developed muscle tremors in all extremities on the fifth day of therapy with intravenous trovafloxacin (200 mg daily). Tremors stopped with drug cessation (Menzies et al, 1999).

H. DELIRIUM

1. CASE REPORTS

a. ACUTE TOXICITY

(1) A 14-year-old female presented in a delirious state with extreme mydriasis and warm and dry skin following ingestion of an unknown amount of ofloxacin, diphenhydramine, and chlormezanone. Both diphenhydramine and chlormezanone plasma concentrations were consistent with therapeutic amounts.

(a) Agitation, hallucination, and anticholinergic symptoms resolved after a trial dose of physostigmine salicylate 2 mg given intravenously (Koppel et al, 1990).

2. DELIRIUM AND VISUAL HALLUCINATIONS have been reported in one HIV positive patient with no prior psychiatric history after receiving CIPROFLOXACIN. It has not been clearly established that delirium and ciprofloxacin are related (Altes et al, 1989).

a. Progressive delirium has also been reported in an elderly patient following the use of ciprofloxacin (Jay & Fitzgerald, 1997).

I. PSYCHOSIS

1. OFLOXACIN -

a. During POST-MARKETING SURVEILLANCE STUDIES of OFLOXACIN, the development of severe neuropsychiatric problems including hallucinations and psychosis were reported. The reactions occurred predominantly in the elderly and may have involved predisposing factors (Ball, 1989; Jungst & Mohr, 1988).

2. CASE REPORT - Neuropsychiatric problems (confusion and massive muscle spasticity) occurred in an 81-year-old female with advanced renal insufficiency after receiving inadvertent concomitant therapy with ofloxacin and pefloxacin at renal doses (Bagon, 1999). Symptoms gradually subsided and the patient was asymptomatic within 8 days of drug cessation.

GASTROINTESTINAL

SUMMARY

A. Abdominal pain, nausea, vomiting, and diarrhea have been reported after overdose and therapeutic use of these agents.

CLINICAL EFFECTS

A. ABDOMINAL PAIN

1. Abdominal pain, dyspepsia, anorexia, vomiting, and nausea have been reported with therapeutic use of these agents (Boerema et al, 1985; Holmes et al, 1985; Ball, 1989; Rahm & Schacht, 1989; Prod Info Trovan(R), 1997; Prod Info Raxar(R), 1997).

2. INCIDENCE - Overall, 2 to 20% of patients receiving fluoroquinolones during therapeutic use experience some type of mild gastrointestinal symptoms (Lipsky & Baker, 1999).

B. DIARRHEA

1. ACUTE TOXICITY

a. SUMMARY - Diarrhea may occur during overdose. It is seen as a mild symptom during therapeutic use of these agents (Boerema et al, 1985; Holmes et al, 1985; Rahm & Schacht, 1989).

2. CHRONIC TOXICITY

a. SPECIFIC SUBSTANCES -

(1) TROVAFLOXACIN - Diarrhea was reported in 2% of patients during clinical trials with oral or injectable forms of trovafloxacin (Prod Info Trovan(R), 1997).

C. NAUSEA VOMITING

1. ACUTE TOXICITY

a. SUMMARY - Nausea and vomiting may occur after minimum exposure to therapeutic doses of fluoroquinolones

b. CASE REPORTS

(1) Nausea and vomiting have been reported after one dose of CIPROFLOXACIN in one HIV positive patient (Altes et al, 1989). It was also seen in a 3 gram IV overdose of OFLOXACIN (Kohler et al, 1991).

2. CHRONIC TOXICITY

a. SPECIFIC SUBSTANCES

(1) GATIFLOXACIN - Nausea has been reported in therapeutic use in healthy volunteers; incidence 13.3% (4 subjects) (Gajjar et al, 2000).

(2) TROVAFLOXACIN - A dose-dependent increase in vomiting was observed in patients during clinical trials with oral and injectable forms of trovafloxacin. Nausea also was reported in both treatment groups with a range of 4% to 8% (Prod Info Trovan(R), 1997).

D. GASTROINTESTINAL DISORDER

1. PSEUDOMEMBRANOUS COLITIS has been reported on rare occasions with both OFLOXACIN and CIPROFLOXACIN (Ball, 1989; Rahm & Schacht, 1989; Jungst & Mohr, 1988).

HEPATIC

SUMMARY

A. Elevated liver enzymes and liver dysfunction have been reported following therapeutic use of fluoroquinolones. Rare, but severe liver injury has been reported with trovafloxacin at therapeutic levels.

CLINICAL EFFECTS

A. HEPATIC ENZYMES INCREASED

1. ANIMAL DATA - Elevated liver function tests were reported after high doses of ENOXACIN, OFLOXACIN, and PEFLOXACIN in rats (Mayer, 1987).

2. CHRONIC TOXICITY

a. INCIDENCE - Liver enzyme abnormalities have been observed in 2% to 3% of patients receiving fluoroquinolone therapy (Lipsky & Baker, 1999). Most elevations in serum transaminase and alkaline phosphatase levels are mild and reversible with discontinuation of treatment.

b. SPECIFIC SUBSTANCES -

(1) CIPROFLOXACIN - Elevated liver enzyme levels were reported after high dose intravenous CIPROFLOXACIN administration in seven hospitalized patients with severe nosocomial infections (Kljucar et al, 1989).

(2) OFLOXACIN - Hepatic dysfunction was reported in several cases in the phase IV trials of OFLOXACIN (Sawada et al, 1991), and was reported in an adult 5 days after the start of therapy (Jones & Smith, 1997).

3. ACUTE TOXICITY

a. NORFLOXACIN - Acute hepatotoxicity induced by NORFLOXACIN has been reported in one patient with no prior history of liver or biliary tract disease (Lopez-Navidae et al, 1990).

B. HEPATIC FUNCTION ABNORMAL

1. SUMMARY -

a. Hepatic injury including hepatitis, acute liver failure and subfulminant hepatic failure (ofloxacin) have been reported with the use of fluoroquinolones in both short and long term use.

2. CASE REPORTS

a. NORFLOXACIN -

(1) Acute cholestatic jaundice was reported in a 70-year-old male following norfloxacin 800 mg/day for 12 days (Lucena et al, 1998). A temporal relationship was suggested; symptoms resolved within one month of exposure.

(2) A 58-year-old with alcoholic liver cirrhosis developed acute cholestatic hepatitis after prophylactic use of norfloxacin (Romero-Gomez et al, 1999). Five days after the start of treatment (400 mg twice daily), jaundice and elevated liver enzymes were observed. Norfloxacin was discontinued with baseline hepatic function returning within one month.

b. OFLOXACIN - Subfulminant hepatic failure was reported in an 70-year-old male following ofloxacin administration (200 mg twice daily) for 5 days; the patient had no known risk factors for liver disease. Fourteen weeks after the development of symptoms the patient had hepatic encephalopathy and died two weeks later (Carro et al, 2000).

c. TROVAFLOXACIN -

(1) The use of trovafloxacin has resulted in the development of liver injury which has led to liver transplantation and/or death. Its use should be limited to 2 weeks duration and reserved for patients with serious life- or limb-threatening infections (Prod Info Trovan(R), 2000).

(2) As of June 1999, the USFDA has issued a warning regarding the possible risks of liver toxicity with trovafloxacin use (Anon, 1999). Currently, 14 cases of acute liver failure have occurred, of which 6 patients died. Labeling changes have been recommended.

(3) Lucena et al (2000) reported three cases of acute hepatitis in adults following the use of trovafloxacin for 7 to 14 days. Other sources of liver injury were ruled out; liver biopsy results suggested an immunoallergic mechanism.

GENITOURINARY

CLINICAL EFFECTS

A. RENAL FUNCTION ABNORMAL

1. ANIMAL DATA - Renal tubular atrophy, interstitial nephritis, tubular dilatation with pigmentation of tubular epithelia, microcrystalluria, and hematuria were observed in laboratory animals exposed to high doses of quinolones (Mayer, 1987).

2. CHRONIC TOXICITY

a. CIPROFLOXACIN - At therapeutic doses hematuria, crystalluria, and interstitial nephritis have been associated with CIPROFLOXACIN therapy in humans. No permanent renal impairment has resulted from ciprofloxacin therapy (Ball, 1989; Hootkins et al, 1989; Garlando et al, 1985).

B.. ACUTE RENAL FAILURE

1. ACUTE TOXICITY

a. CASE REPORTS

(1) CIPROFLOXACIN - A 15-year-old suicidal female ingested 7.5 to 10 g (15 to 20 tablets) of ciprofloxacin and 100 mg of trazodone 24 hours prior to hospital admission. The patient's BUN and creatinine (Cr) rose initially with a persistent rise in Cr. Cr peaked on hospital day 6 to 6.2 mg/dL with anuria. Electron microscopic studies showed distal nephron apoptosis. One week after ingestion, Cr had decreased and laboratory studies were within normal limits within 3 months (Dharnidharka et al, 1998).

C. VAGINITIS

1. CHRONIC TOXICITY

a. SUMMARY - Vaginitis has been associated with the therapeutic use of CIPROFLOXACIN (Rahm & Schacht, 1989) and TROVAFLOXACIN (Prod Info Trovan(R), 1997).

HEMATOLOGIC

SUMMARY

A. Hematologic toxicity has been reported infrequently with therapeutic use of fluoroquinolones.

CLINICAL EFFECTS

A. ANEMIA

1. ANIMAL DATA - High doses of PEFLOXACIN and ENOXACIN have been associated with the development of anemia in animal studies (Mayer, 1987).

B. EOSINOPHILIA

1. CHRONIC TOXICITY

a. CIPROFLOXACIN - Eosinophilia and leukopenia have been associated with the therapeutic use of CIPROFLOXACIN (Rahm & Schacht, 1989; Choo & Gantz, 1990).

C. LEUKOPENIA

1. TROVAFLOXACIN - Leukopenia (2.2 x 10(3)/mm(3)) was reported in an elderly patient following 5 days of intravenous trovafloxacin therapy following a traumatic leg amputation. Laboratory studies improved after drug cessation (Mitropoulos et al, 2001).

D. THROMBOCYTOPENIA

1. TROVAFLOXACIN - An adult female developed thrombocytopenia following 3 days of intravenous alatrofloxacin (prodrug of trovafloxacin; 300 mg daily). Bleeding (epistaxis) and petechiae on the oral mucous membranes, were reported along with a platelet count of 7 and 2 x 10(3)/mm(3) on hospital day 4 and 5 respectively. Clinical signs and symptoms improved with the discontinuation of alatrofloxacin (Gales & Sulak, 2000).

Additional ADRS:

Asthenia

Edema

Fever

Malaise

Rigors

Substernal Chest Pain

Syncope

Cardiovascular Disorders

Cardiac Failure

Circulatory Failure

Hypertension

Central and Peripheral Nervous System Disorders

Abnormal Coordination

Coma

Convulsions

Seizures

Hyperkinesia

Hypertonia

Hypoaesthesia

Involuntary Muscle Contractions

Paresthesia

Paralysis

Speech Disorders

Stupor

Tremor

Vertigo

Gastrointestinal System Disorders

Dry Mouth

Dysphagia

Gastroenteritis

G.I.Hemorrhage

Pancreatitis

Pseudomembranous Colitis

Tongue Edema

Hearing and Vestibular Disorders

Ear Disorders

Tinnitus

Heart Rate and Rhythm Disorders

Arrhythmia

Atrial Fibrillation

Bradycardia

Cardiac Arrest

Heart Block

Palpitation

Supraventricular Tachycardia

Tachycardia

Ventricular Fibrillation

Hematology

Decreased Lymphocytes

Liver and Biliary System Disorders

Abnormal Hepatic Function

Cholelithiasis

Hepatic Coma

Jaundice

Metabolic and Nutritional Disorders

Aggravated Diabetes

Mellitus

Decreased Glucose

Decreased Magnesium

Increased Calcium

Dehydration

Hyperglycemia

Hyperkalemia

Hypoglycemia

Hypokalemia

Increased LDH

Weight Loss

Musculo-Skeletal System Disorders

Arthralgia

Arthritis

Arthrosis

Muscle Weakness

Myalgia

Osteromyelitis

Rhabdomyolysis

Synovitis

Tendinitis

Myo, Endo, Pericardial and Valve Disorders

Angina

Pectoris

Coronary Thrombosis

Myocardial Infarction

Neoplasms

Carcinoma

Parosmia

Platelet, Bleeding and Clotting Disorders

Abnormal Platelets

Embolism

Epistaxis

Purpura

Thrombocytopenia

Psychiatric Disorders

Abnormal Dreaming

Aggressive Reaction

Agitation

Anorexia

Anxiety

Confusion

Delirium

Depression

Emotional Liability

Hallucination

Impaired Concentration

Impotence

Manic Reaction

Mental Deficiency

Nervousness

Paranoia

Sleep Disorders

Somnolence

Withdrawal Syndrome

Suicide

Red Blood Cell Disorders

Anemia

Reproductive Disorders

Ejaculation Failure

Resistance Mechanism Disorders

Fungal Infections

Genital Moniliasis

Respiratory System Disorders

ARDS

Asthma

Coughing

Dyspnea

Haemoptysis

Hypoxia

Pleural Effusion

Respiratory Insufficiency

Respiratory Failure

Skin and Appendages Disorders

Erythema Nodosum

Genital Pruritus

Increased Sweating

Skin Disorders

Skin Exfoliation

Skin Ulceration

Urticaria

Urinary System Disorders

Abnormal Renal Function

Acute Renal Failure

Face Edema

Crystalluria

Cylindruria

Hematuria

Vascular (Extracardiac) Disorders

Cerebrovascular Disorder

Phlebitis

Vision Disorders

Abnormal Vision

Conjunctivitis

Diplopia

Retina Damage

Cornea Damage

Ophthalmologic Abnormalities

Cataracts

Multiple Punctate Lenticular Opacities

White Cell and RES Disorders

Granulocytopenia

Leukocytosis

Leukopenia

Lymphadenopathy

WBC Abnormal Count

Allergic Pneumonitis

Anaphylactic Shock

Anaphylactoid Reaction

Dysphonia

Abnormal EEG

Encephalopathy

Eosinophilia

Erythema Multiforme

Hemolytic Anemia

Multi System Organ Failure (Death)

Increased International Normalized Ratio (INR) Prothrombin Time

Stevens-Johnson Syndrome

Tendon Rupture

Torsades de Pointes

Vasodilation

This is but a small sampling of various adverse reactions associated with such therapy. This list goes on and on and on and on and on. 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 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 later we find no such warnings regarding this PERMANENT DISABILITY 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.

"...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, together with those responsible for the manufacture, sale and distribution of this toxic poison. 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 Bristrol-Meyers 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

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. 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. Congress must investigate why the have failed so miserably regarding fluoroquinolones.





Sincerely yours,



Director

Fluoroquinolone Toxicity Research Foundation

www.fqresearch.org