The Fluoroquinolone Toxicity Research Foundation

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Grepafloxacin

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All brand names are trademarks of their respected manufacturers. The information being provided below is to be considered a quick reference guide. For complete information please view the complete package insert at www.rxlist.com or by entering the drug name at Drugs@FDA

Grepafloxacin

Brand Names: Raxar

Removed from clinical use due to severe toxicity (ie: qt time)

RAXAR:Warning on Label Omits Deaths http://www.latimes.com/news/nation/reports/fda/lat_raxar001220.htm
Heart problems were mentioned in fine print, but not key dosage data. By DAVID WILLMAN, Times Staff Writer

Peripheral Neuropathy
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones.

QUINOLONES MAY HAVE THE POTENTIAL TO PROLONG THE QTc INTERVAL OF THE ELECTROCARDIOGRAM IN SOME PATIENTS. DUE TO THE LACK OF CLINICAL EXPERIENCE, GATIFLOXACIN SHOULD BE AVOIDED IN PATIENTS WITH KNOWN PROLONGATION OF THE QTc INTERVAL, PATIENTS WITH UNCORRECTED HYPOKALEMIA, AND PATIENTS RECEIVING CLASS IA (E.G. QUINIDINE, PROCAINAMIDE) OR CLASS III (E.G. AMIODARONE, SOTALOL) ANTIARRHYTHMIC AGENTS.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Tendon rupture can occur during or after therapy with quinolones.

Quinolones may cause central nervous system (CNS) events including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia.

As with other quinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic (e. g., glyburide) or with insulin. In these patients, the monitoring of blood glucose is recommended.

Glaxo Wellcome voluntarily withdraws Raxar (Grepafloxacin)

Glaxo Wellcome plc announces that it is voluntarily withdrawing its oral fluoroquinolone antibiotic, Raxar (grepafloxacin), with immediate effect, as a result of emerging safety concerns. In coming to this decision the company has recognised the need to strike a balance between the therapeutic benefits of the medicine, the potential risk of side effects, and the availability of alternative treatments.

An estimated 2.65 million patient treatments have been prescribed since Raxar was first marketed in August 1997. In line with the company’s practice, Glaxo Wellcome has monitored the safety profile of Raxar since launch, and has observed a small number of severe cardiovascular events among patients. While the reported incidence of such cardiovascular events is infrequent, the company is no longer convinced that the benefits of Raxar outweigh the potential risk to patients, given the availability of alternative antibiotics.

Glaxo Wellcome has discussed the safety profile of Raxar with the appropriate regulatory authorities and cardiovascular medical specialists. The decision to withdraw the medicine has been taken on the recommendation of Glaxo Wellcome’s senior medical review group, and the company is in the process of informing doctors and pharmacists of the decision in countries where Raxar is marketed.

Raxar is indicated for the treatment of a variety of infections including pneumonia, bronchitis, and some sexually transmitted infections. Glaxo Wellcome licensed Raxar from Otsuka in 1996, and currently markets the medicine in tablet form in over 30 countries, primarily in Europe, North America and Latin America. A co-marketing agreement exists between the two companies in Spain. The medicine is marketed as Raxar or Vaxar.

Glaxo Wellcome is a research-based company whose people are committed to fighting disease by bringing innovative medicines and services to patients throughout the world and to the healthcare providers who serve them.

ANIMAL PHARMACOLOGY

Quinolones have been shown to cause arthropathies in juvenile rats and dogs. Grepafloxacin-associated joint toxicity (cavitation with loss of cartilaginous matrix and chondrocytes with cartilage fibrillation) was observed in juvenile dogs Grepafloxacin associated joint toxicity (blisters of the articular cartilage) was observed in juvenile dogs.

In the dog, oral doses caused prolongation of the QT interval, although the results were variable. Intravenous administration of grepafloxacin elicited a moderate hypotension in anesthetized dogs and rabbits.

Phototoxic reactions have been reported with other quinolones.

Lenticular opacities, sometimes observed with other quinolones.

Drug interactions resulting in seizures have been reported between some quinolones and NSAIDs.

Additional drug-related events:

Body as a Whole: Back pain, body odor, chest pain, chills, facial edema, fever, malaise, neck rigidity, pelvic pain.
Cardiovascular System: Arrhythmia, hypotension, palpitations, peripheral vascular disorder, postural hypotension, syncope, tachycardia, vasodilatation.
Digestive System: Abnormal liver function tests, abnormal stools, cheilitis, dysphagia, eructation, flatulence, gastritis, gastrointestinal disorder, gingivitis, glossitis, increased appetite, melena, mouth ulceration, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue discoloration, tongue disorder, tongue edema.
Hemic and Lymphatic System: Anemia, eosinophilia, hypochromic, anemia, leukocytosis, leukopenia, lymphadenopathy, lymphocytosis, lymphoma like reaction, prothrombin decreased, prothrombin increased, reticuloendothelial hyperplasia, thrombocytopenia, thromboplastin increased.
Metabolic and Nutritional System: Dehydration, edema, electrolyte abnormality, gout, hyperglycemia, hyperlipidemia, hypernatremia, hyperuricemia, increased alkaline phosphatase, increased BUN, increased creatinine, increased gamma glutamyl transpeptidase, increased SGOT, increased SGPT, peripheral edema, weight loss.
Musculoskeletal System: Arthralgia, myalgia.
Nervous System: Abnormal dreams, abnormal gait, agitation, anxiety, confusion, depression, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, paresthesia, speech disorder, stupor, thinking abnormal, tremor, vertigo.
Respiratory System: Asthma, atelectasis, bronchitis, dyspnea, epistaxis, hemoptysis, increased cough, laryngismus, pharyngitis, pleural effusion, rhinitis, sputum increased.
Skin and Appendages: Acne, alopecia, dry skin, epidermal necrolysis, exfoliative dermatitis, fungal dermatitis, herpes simplex, maculopapular rash, skin disorder, sweating, urticaria, vesiculobullous rash.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear disorder, eye pain, lacrimation disorder, parosmia, photophobia, taste loss, tinnitus.
Urogenital System: Albuminuria, balanitis, dysuria, hematuria, impotence, polyuria, urethral pain, uricaciduria, urinary frequency, urinary tract disorder, urination impaired, urine abnormality, vulvovaginal disorder.

Additional drug-related events occurring in single dose clinical trials: Body as a Whole: Asthenia, chest pain, chills, flu-like syndrome, infection, malaise.

Eye: Disturbances in vision.

Non Site specific: Allergic reactions, including anaphylactoid reaction/anaphylactic shock, angioedema, laryngeal edema.

Grepafloxacin, like other quinolones, may inhibit the metabolism of caffeine and theobromine. These stimulants are commonly found in coffee and tea, respectively. In some patients, this may lead to reduced clearance, prolongation of plasma half-life, and enhanced effects of caffeine and theobromine.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
The concomitant administration of a nonsteroidal anti inflammatory drug with a quinolone may increase the risks of CNS stimulation and convulsions

Histopathological examination of the weight bearing joints of juvenile dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, or hallucinations.

In healthy male and female volunteers who received RAXAR, prolongation of the QT_c interval was observed

Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions have been reported in patients receiving therapy with quinolones, often following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension, shock, seizure, loss of consciousness, tingling, angioedema, (including tongue, laryngeal, throat, or facial edema/swelling, etc.), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria/hives, itching, and other serious skin reactions.

Serious and sometimes fatal events of uncertain etiology have been reported in patients receiving therapy with quinolones. Serious events are extremely rare and generally occur following administration of multiple doses. Clinical manifestations of serious adverse events may include one or more of the following: fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, etc.); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis; interstitial nephritis, acute renal insufficiency/failure; hepatitis, jaundice, acute hepatic necrosis/failure; tendon pain, inflammation, or rupture; anemia (including hemolytic and aplastic anemia) thrombocytopenia, including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including quinolones, and may range in severity from mild to life-threatening.

Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolone antibiotics.

Phototoxicity reactions have been observed in patients who were exposed to direct sunlight or tanning booths while receiving some quinolones including grepafloxacin. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.

Grepafloxacin increases the effects of theophylline, and to advise their physician immediately if they are taking theophylline.

Grepafloxacin may increase the effects of other drugs metabolized by the liver, and to advise their physician of any of the drugs they are taking.

Grepafloxacin may increase the effects of caffeine.

Grepafloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of skin rash, hives, or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, or any other symptom of an allergic reaction.

Grepafloxacin may cause dizziness and lightheadedness

Caffeine Theobromine: Grepafloxacin, like other quinolones, may inhibit the metabolism of caffeine and theobromine. These stimulants are commonly found in coffee and tea, respectively. In some patients, this may lead to reduced clearance, prolongation of plasma half-life, and enhanced effects of caffeine and theobromine.

Nonsteroidal Anti inflammatory Drugs (NSAIDs): The concomitant administration of a nonsteroidal anti inflammatory drug with a quinolone may increase the risks of CNS stimulation and convulsions.

Grepafloxacin is excreted in human milk.