Maxaquin
  Lomefloxacin
  G.D. Searle LLC  A subsidiary of Pharmacia Corporation
  (NDA 020013
  Latest Package Insert
  Lomefloxacin 1999,  2004, 2005
  Safety Profile

  DO NOT USE 

Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- March 2005

Maxaquin (lomefloxacin hydrochloride tablets)

WARNINGS Peripheral Neuropathy Tendon Effects
PRECAUTIONS Information for Patients
ADVERSE REACTIONS Post-Marketing Adverse Events Quinolone-Class Adverse Events Peripheral Neuropathy Torsades de Pointes

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, including lomefloxacin. Lomefloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and /or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Tendon Effects
Ruptures of the shoulder, hand, Achilles tendon or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including lomefloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Lomefloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendonitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones, including lomefloxacin.

http://www.fda.gov/cder/foi/appletter/2005/20013s015ltr.pdf

DEPARTMENT OF HEALTH & HUMAN SERVICES
Food and Drug Administration
Rockville, MD 20857
NDA 20-013/S-015
 

Pfizer, Inc.
Attention: Mr. Robert Clark
Vice President, U.S. Regulatory Strategy
235 East 42 nd Street
New York, NY 10017

Dear Ms. Gamper:

Please refer to your supplemental new drug application dated April 9, 2004, received April 12, 2004, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for MAXAQUIN ®
(lomefloxacin hydrochloride) Tablets, 400 mg. Your submission of February 4, 2005 constituted a complete response to our October 8, 2004 action letter.
This “Changes Being Effected” supplemental new drug application provides for the following revisions to the package insert (additions are double underlined and deletions are in strikethrough):

1. WARNINGS
• The following paragraph was added for peripheral neuropathy:
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, including lomefloxacin. Lomefloxacin should be discontinued if the
patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and /or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

• The tendon rupture paragraph was revised to read:

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including lomefloxacin. Post-marketing surveillance reports
indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Lomefloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendonitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones, including lomefloxacin.

2. PRECAUTIONS
• A peripheral neuropathy bullet was added under Information for Patients as follows;
o that peripheral neuropathies have been associated with lomefloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, they should discontinue treatment and contact their physicians.

3. ADVERSE REACTIONS
• The header “Quinolone class adverse events” was deleted and replaced with the header “Post-Marketing Adverse Events”.
• Peripheral neuropathy and torsades de pointes were added to the Quinolone-class adverse events subsection to read:
Quinolone-class adverse events: Additional quinolone-class adverse events include: Peripheral neuropathy, torsades de pointes, erythema nodosum, hepatic necrosis, possible exacerbation of myasthenia gravis, dysphasia, nystagmus, intestinal perforation, manic reaction, renal calculi, acidosis and hiccough.

We have completed the review of this supplemental new drug application, as amended, and have concluded that adequate information has been presented to demonstrate that the drug product is safe and effective for use as recommended in the agreed upon labeling text (enclosed). Accordingly, this
supplemental application is approved effective on the date of this letter.

The final printed labeling (FPL) must be identical to the submitted draft labeling (text for the package insert submitted February 4, 2005). Please submit an electronic version of the FPL according to the guidance for industry titled Providing Regulatory Submission in Electronic Format – NDA. Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15 of the copies on heavy-weight paper or similar material. For administrative purposes, designate this submission as "FPL for approved supplement NDA 20-013/S-015." Approval of this submission by FDA is not required before the labeling is used.

If you issue a letter communicating important information about this drug product (i.e., a "Dear Health Care Professional" letter), we request that you submit a copy of the letter to this NDA and a copy to the following address:

MEDWATCH, HF-2
FDA
5600 Fishers Lane
Rockville, MD 20857
We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR 314.80 and 314.81.
If you have any questions, call Robin Anderson, R.N., M.B.A., Labeling Reviewer, at (301) 827-2127.

Sincerely,
{See appended electronic signature page}
Renata Albrecht, M.D.
Director
Division of Special Pathogen and Immunologic Drug
Products
Office of Drug Evaluation IV
Center for Drug Evaluation and Research

FDA Safety Labeling Changes: Maxaquin
Yael Waknine;

June 15, 2005 — The U.S. Food and Drug Administration (FDA) approved in March revisions to safety labeling to advise that use of lomefloxacin HCl tablets is associated with a risk of peripheral neuropathy and tendon effects; use of temozolomide capsules is associated rarely with the development of secondary malignancies; and use of oxcarbazepine tablets and oral solution is associated with a risk of serious hypersensitivity reactions in adults and children.

Lomefloxacin HCl (Maxaquin) Linked to Risk of Peripheral Neuropathy, Tendon Effects

On March 16, the FDA approved revisions to the safety labeling for lomefloxacin HCl (Maxaquin tablets, made by Pfizer, Inc.), warning of the risk of peripheral neuropathy and tendon effects associated with its use.

The FDA has received rare postmarketing reports of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons and resulting in paresthesias, hypoesthesias, dysesthesias, and weakness in patients receiving quinolones, including lomefloxacin.

To prevent the development of an irreversible condition, lomefloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, or having deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength.

Ruptures of shoulder, hand, Achilles, and other tendons resulting in prolonged disability or requiring surgical repair have also been reported in patients receiving quinolones such as lomefloxacin. According to the FDA, the reports indicate that risk of tendon rupture may be increased in patients receiving concomitant steroids, particularly in those of advanced age.

Lomefloxacin should be discontinued in patients experiencing pain, inflammation, or tendon rupture. Patients should rest and refrain from exercise until tendonitis and tendon rupture have been excluded from the diagnosis.

Lomefloxacin HCl is a fluoroquinolone antibiotic indicated for the treatment of adults with mild to moderate lower respiratory tract and urinary tract infections caused by susceptible Gram-negative and Gram-positive bacterial strains, and preoperatively for the prevention of urinary tract infection from transrectal prostate biopsy and transurethral surgical procedure.

Other adverse reactions associated with the fluoroquinolones

Peripheral Neuropathy
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, QUINOLONES 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.

In 2004 new warning labels added to all of the Fluoroquinolones regarding Peripheral Neuropathy (irreversible nerve damage), Tendon Damage, Heart Problems (prolonged QT Interval / Torsades de pointes), Pseudomembranous colitis, Rhabdomyolysis (muscle wasting), Steven Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.
.
Although such events have been reported since the mid sixties, the FDA waited almost forty years to add such warnings to the package inserts.  These new warnings again fail to adequately warn either the patient or the physician.

"Drug companies write the package inserts of all drugs, carefully including the information they choose and
omitting information they want to avoid. Drug companies underwrite a large percentage of continuing
education courses for doctors. In doing so, they make sure that the speakers represent the company view.
Drug companies design studies that are meant to produce favorable results and then publish the studies in
medical journals. Studies with unfavorable results are not published. Drug reps typically bring stacks of
studies, all favorable, which impress doctors, who no longer have the time or motivation to search  the
medical literature themselves. Drug reps do not include independent studies with less favorable
conclusions. Many doctors never see these." 

Source:   THE MEDICAL PROFESSION AND THE CULTURE OF CORRUPTION

PERIPHERAL NEUROPATHY (as noted above)
Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability.
Convulsions, increased intracranial pressure, and toxic psychosis.
Central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, ly, suicidal thoughts or acts. These reactions may occur following the first dose.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome
Pseudomembranous colitis and may range in severity from mild to life-threatening.
Lameness in immature dogs with permanent lesions of the cartilage.
Central nervous system (CNS) events, including nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
Crystalluria
Moderate to severe photoxicity

Additional adverse events reported:

Body as a Whole: Change in serum phenytoin.

Cardiovascular: Palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thromobosis. Cardiovascular collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina pectoris. Postural hypotension, vasculitis.

Central Nervous System: Dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia. Convulsive seizures, paranoia, toxic psychosis, depression, dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness, irritability, malaise, lethargy Agitation, confusion, delirium, dysphasia, myoclonus, nystagmus, toxic psychosis.
.
Gastrointestinal: Painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding. Cholestatic jaundice has been reported. Ileus, jaundice, gastrointestinal bleeding, C. difficle associated diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric or abdominal pain, vomiting, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence Constipation, dyspepsia, flatulence, hepatic necrosis, jaundice, pancreatitis, pseudomembranous colitis. (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.)

Hemic/Lymphatic: Agranulocytosis, hemolytic anemia, methemaglobinemia, prolongation of prothrombin time

Metabolic/Nutritional: Elevation of serum triglycerides, cholesterol, blood glucose, serum potassium.

Musculoskeletal: Arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout. Arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain, achiness, flare up of gout Myalgia, possible exacerbation of myasthenia gravis, tendinitis/tendon rupture.

Renal/Urogenital: Interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis. Renal failure, intarstitial nephritis, hemorrhagic cystitis, renal calcuti, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia, candiduria, vaginitis. Crystalluria, cylindruria, hematuria, and albuminutia have also been reported.
Albuminuria, candiduria, renal calculi, vaginal candidiasis.

Respiratory: Dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemophysis, bronchospasm, pulmonary embolism. Respiratory arrest, pulmonary embolism, dyspnea, pulmonary edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough

Skin/Hypersensitivity: Pruritus, urticaria, photosensitivity, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erytherna nodosum. Allergic reactions ranging from urticaria to anaphylactic reactions have been reported. Anaphylactic reactions, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever, chills, flushing, pruritus, urtigaria, cutaneous candidiasis, vesicles, increased perspiration, hyperpigmentation, erythema nodosum, photosensitivity. Allergic reactions ranging from urticaria to anaphylactic reactions have been reported. Anaphylactic reactions, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis.

Special Senses: Blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste. Decreased visual acuity, blurred vision, disturbed vision (flashing lights, change in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, a bad taste. Also reported were agranulocytosis, prolongation of prothrombin time, and possible exacerbation of myasthenia gravis. anosmia, taste loss.
 

Adverse Laboratory Changes

Oral

Changes in Laboratory Parameters Listed as Adverse Events:

Other changes occurring ly during administration of fluoroquinolone were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
 

ANIMAL PHARMACOLOGY
Oral and I.V.