Product Manual: TOPLEVO

PRODUCT BRIEF
NAME OF THE PRODUCT Brand Name Generic Name : :

Toplevo
Levofloxacin INN.

DOSAGE FORM & STRENGTH OF THE PRODUCT 1. Tablet : Levofloxacin 500 mg

DESCRIPTION OF THE PRODUCT

1. Toplevo 500F
Presentation Packing Pack Size : : : Round shaped tablet with off white color. Alu-Alu Blister of 10 Tablets. 3 10 Tablets in a box.

History
1

Product Manual: TOPLEVO Levofloxacin was first patented in 1987 by the Daiichi Pharmaceutical Co. Ltd. (now Daiichi Seiyaku Pharmaceutical Co. Ltd - one of Japan's largest pharmaceutical companies. Levofloxacin has been developed to take advantage of antibacterial potency requiring only about half the usual dose of ofloxacin. Levofloxacin was first launched in Japan in 1993 under the brand name Cravit. Levofloxacin was approved by the United States Food and Drug Administration on December 20, 1996 by Ortho McNeil Pharmaceutical under the name Levaquin, for use in the United States to treat severe and life-threatening bacterial infections. Ranking 37th within the top 200 prescribed drugs in the United States for 2007 and ranked 19th in world sales in 2007, total sales for Levaquin were in excess of 1.6 billion dollars. Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.

Description
Toplevo (Levofloxacin) is a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, Toplevo (Levofloxacin) is a chiral fluorinated carboxyquinolone, and the pure (-)-(S)-enantiomer of ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxazine6-carboxylic acid hemihydrate.

Chemical Properties
The empirical formula is C18H20FN3O4 H2O and the molecular weight is 370.38. Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a zwitter ion at the pH conditions in the small intestine. From pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9. Levofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al+3 > Cu+2 > Zn+2 > Mg+2 > Ca+2.

Product Manual: TOPLEVO

Pharmacokinetics
Absorption Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of Levofloxacin are both approximately 99%, Distribution The mean volume of distribution of levofloxacin ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of at approximately 3 hours after dosing. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5- fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose. Levofloxacin is approximately 24 to 38% bound to serum proteins. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration. Metabolism Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity. Excretion Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving Levofloxacin.

Mechanism of action
Levofloxacin is a bactericidal antibiotic (kills the bacteria). It inhibits DNA-gyrase in susceptible organisms thereby inhibits relaxation of supercoiled DNA and promotes breakage of DNA strands. DNA gyrase (topoisomerase II), is an essential bacterial enzyme that maintains the superhelical structure of DNA and is required for DNA replication and transcription, DNA repair, recombination, and transposition.

Product Manual: TOPLEVO

Indication
Levofloxacin is indicated for the treatment of adults ( 18 years of age) with mild, moderate, and severe infections caused by susceptible strains of the designated microorganisms in the conditions listed in this section. o Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. o Acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis. o Nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal b-lactam is recommended. o Community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae. o Complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis. o Uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes. o Chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis. o Complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa. o Acute pyelonephritis (mild to moderate) caused by Escherichia coli. o Uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae or Staphylococcus saprophyticus. o Inhalational anthrax (post-exposure) - to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis

Dosage Schedule
The usual dose of Levofloxacin Tablets is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. These recommendations apply to patients with creatinine clearance 50 mL/min. For patients with creatinine clearance < 50 mL/min, adjustments to the dosing regimen are required.

Product Manual: TOPLEVO

Dosage in Adult Patients with Normal Renal Function Type of Infection Nosocomial Pneumonia Community Acquired Pneumonia Community Acquired Pneumonia Acute Bacterial Sinusitis Acute Bacterial Exacerbation of Chronic Bronchitis Complicated Skin and Skin Structure Infections Uncomplicated SSSI Chronic Bacterial Prostatitis Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) Uncomplicated Urinary Tract Infection Inhalational Anthrax (Post-Exposure), adult and Every 24 hours 750 mg 500 mg 750 mg 750 mg 500 mg 500 mg 750 mg 500 mg 500 mg 750 mg 250 mg 250 mg 500 mg Duration (days) 7-14 7-14 5 10-14 7 7-14 7-10 28 5 10 3 60

Dosage in Pediatric Patients 6 months of age Type of Infection Inhalational Anthrax (post-exposure) Pediatric patients > 50 kg and 6 months of age Pediatric patients < 50 kg and 6 months of age 500 mg 8 mg/kg (not to exceed 250 24hr 12hr 60 days 60 days Dose Frequency Duration

Product Manual: TOPLEVO mg per dose)

Side Effects
Tendinopathy and Tendon Rupture Toplevo increases risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including levofloxacin. These reactions often occur 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), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Hepatotoxicity Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Central Nervous System Effects Convulsions and toxic psychoses have been reported in patients receiving fluoroquinolones, including Levofloxacin. Fluoroquinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Levofloxacin and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. 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 fluoroquinolones, including Levofloxacin. Prolongation of the QT Interval

Product Manual: TOPLEVO Levofloxacin have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving Levofloxacin. Musculoskeletal Disorders in Pediatric Patients Levofloxacin is indicated in pediatric patients ( 6 months of age) only for the prevention of inhalational anthrax (post-exposure). An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levofloxacin Blood Glucose Disturbances As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyperand hypoglycemia, have been reported with Levofloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, V area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of Levofloxacin after sun or UV light exposure. Development of Drug Resistant Bacteria Prescribing Levofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria

Drug Interaction
Chelation Agents: Concurrent administration of Levofloxacin with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Warfarin No apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that Levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and Levofloxacin use have been associated with episodes of bleeding. Prothrombin time. Antidiabetic Agents

Product Manual: TOPLEVO Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with Levofloxacin and an antidiabetic agent. Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a Levofloxacin may increase the risk of CNS stimulation and convulsive seizures. Theophylline Concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Cyclosporine Elevated serum levels of cyclosporine have been reported in the patient when coadministered with some other fluoroquinolones. Levofloxacin Cmax and ke were slightly lower while Tmax and t1/2 were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. Digoxin No significant effect of Levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for Levofloxacin or digoxin is required when administered concomitantly. Probenecid and Cimetidine No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t1/2 of levofloxacin were higher while CL/F and CLR were lower during concomitant treatment of Levofloxacin with probenecid or cimetidine compared to Levofloxacin alone. Interactions with Laboratory or Diagnostic Testing Levofloxacin may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

Contraindication
Toplevo (Levofloxacin) is contraindicated in patients with a known hypersensitivity to levofloxacin or other quinolone drugs. It is also contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance. Levofloxacin is also considered to be contraindicated in patients with epilepsy or other seizure disorders.

Product Manual: TOPLEVO

Use in specific population

Pregnancy Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area. There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Based on data on other fluoroquinolones and very limited data on Levofloxacin, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from Levofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Levofloxacin causes arthropathy and osteochondrosis in juvenile animals of several species. Levofloxacin is indicated in pediatric patients ( 6 months of age) only for the prevention of inhalational anthrax (post-exposure) Inhalational Anthrax (Post-Exposure) Levofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied. The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with Levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendonitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after Levofloxacin treatment have been reported. 9

Product Manual: TOPLEVO

Renal Impairment Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of Levofloxacin are not required following hemodialysis or CAPD. Hepatic Impairment Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

Over Dose
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis. Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of Levofloxacin : ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.

Warnings and Precautions

Tendinopathy and Tendon Rupture Levofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a nonquinolone antimicrobial drug. Hypersensitivity Reactions Levofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated

10

Product Manual: TOPLEVO

Hepatotoxicity The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis Central Nervous System Effects Levofloxacin should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction Clostridium difficile-Associated Diarrhea If Clostridium difficile-associated diarrhea (CDAD) is suspected or confirmed, ongoing antibiotic use not directed against C difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral Neuropathy Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition. Prolongation of the QT Interval Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Musculoskeletal Disorders in Pediatric Patients Levofloxacin is indicated in pediatric patients ( 6 months of age) only for the prevention of inhalational anthrax (post-exposure). An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levofloxacin. Blood Glucose Disturbances In diabetic patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with Levofloxacin, Levofloxacin should be discontinued and appropriate therapy should be initiated immediately. Photosensitivity/Phototoxicity

11

Product Manual: TOPLEVO Excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs

Storage
Store at room temperature between 59-86 degrees F (15-30 degrees C) in a tightly closed container away from light and moisture. Do not store in the bathroom. Keep all medicines away from children. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed.

Advantages and Disadvantages

Advantages Toplevo (Levofloxacin) is convenient once-daily dosing - this is of particular benefit in those patients who may not be compliant Toplevo (Levofloxacin) is rapidly bactericidal with a broad spectrum of activity Toplevo (Levofloxacin) is better safety and tolerability- one of the least likely fluoroquinolones to cause any cardiovascular effects, central nervous system disturbances and phototoxicity Toplevo (Levofloxacin) has less significant drug interactions than with other fluoroquinolones, as levofloxacin does not have a major P-450 metabolism Toplevo (Levofloxacin) has relatively low emergence of resistant organisms Toplevo (Levofloxacin) shows expanded gram-positive spectrum of activity (including Streptococcus pneumoniae) Toplevo (Levofloxacin) provides moderate anaerobic activity (most quinolones possess weak activity against anaerobes) Toplevo (Levofloxacin) is currently the only respiratory fluoroquinolone approved for the treatment of nosocomial pneumonia Toplevo (Levofloxacin) has excellent bioavailability about 99% after oral administration Treatment of acute exacerbations of chronic obstructive pulmonary disease with Toplevo (Levofloxacin) may reduce hospitalizations compared with standard antibiotics Toplevo (Levofloxacin) may be a good choice in persons with liver disease in whom other fluoroquinolones are contraindicated Toplevo (Levofloxacin) does not interact with alcohol Disadvantages: Toplevo (Levofloxacin) is not active against methicillin-resistant staphylococci, including S. aureus, S. epidermidis and S. haemolyticus Toplevo (Levofloxacin) has the risk of tendon ruptures (this risk may be increased in persons taking corticosteroids, especially the elderly)

12

Product Manual: TOPLEVO Toplevo (Levofloxacin) has risk of peripheral neuropathy (nerve damage), the symptoms include pain, burning, tingling, numbness, weakness, other alterations of sensation Toplevo (Levofloxacin) has risk of prolongation of the QT interval, arrhythmia, and rare cases of torsades de pointes Toplevo (Levofloxacin) exerts central nervous system and psychiatric side effects, such as convulsions, confusion, anxiety, depression, and insomnia Toplevo (Levofloxacin) may delay the fracture healing. Use of levofloxacin during early fracture repair may compromise the clinical course of fracture-healing.

Comperison with Other drugs

Levofloxacin versus Other Medications According to the studies, the rank order of phototoxic potential of fluoroquinolones is as follows: enoxacin> ciprofloxacin > norfloxacin = ofloxacin = levofloxacin = gatifloxacin = moxifloxacin Based on published literature, the approximate order of fluoroquinolones in which they significantly interact with theophylline is as follows: enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin. Levofloxacin was found to be very safe with a low rate of hepatic abnormalities (1/650,000). Levofloxacin, ofloxacin, and moxifloxacin reportedly have the lowest potential of inducing central nervous system (CNS) adverse events among the fluoroquinolones currently available. Cardiovascular problems were seen in 1/15 million levofloxacin prescriptions compared to 13% of sparfloxacin patients having QTc prolongation of greater than 500 msec. Moxifloxacin was also associated with QTc prolongation when compared to non-fluoroquinolone comparators. Nausea, vomiting, and diarrhoea remain the main adverse drug reactions associated with levofloxacin. However, the ADR rate for levofloxacin is still one of the lowest of any fluoroquinolone at 2% (compared to 2-10% for other fluoroquinolones). The tolerance profile of levofloxacin can be considered to be very good, and better than most, if not all of the fluoroquinolones available. Levofloxacin vs. Ciprofloxacin Skin and Skin Structure Infections: Among 253 patients (129 levofloxacin, 124 ciprofloxacin), clinical success (cure and improvement) was observed in 96.1% of levofloxacin-treated patients and in 93.5% of ciprofloxacin-treated patients. Bacteriological eradication rates by pathogen were 93.2% and 91.7%, respectively. Levofloxacin eradicated 94% (66/70) of Staphylococcus aureus and 94% (17/18) of Streptococcus pyogenes isolates, compared with 93% (70/75) and 92% (12/13) for ciprofloxacin. Microbiological eradication rates by subject were approximately

13

Product Manual: TOPLEVO 93% and 90% for the levofloxacin and ciprofloxacin groups, respectively. Drug-related adverse events were reported by 8.9% of those receiving levofloxacin and 8.2% of those administered ciprofloxacin Acute Pyelonephritis, Urinary tract infections (UTI): Levofloxacin 750 mg once daily for 5 days is at least as effective as ciprofloxacin 400 mg or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis 13. In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference 3.4, 95% CI 14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference 0.9, 95% CI 7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin. Chronic bacterial prostatitis: Levofloxacin 500 mg once daily for 28 days is as effective as ciprofloxacin 500 mg twice daily for 28 days for the treatment of chronic bacterial prostatitis. The clinical success rates, including cured plus improved patients, were similar (75% for levofloxacin and 72.8% for ciprofloxacin). Microbiologic eradication rates were 75% for levofloxacin and 76.8% for ciprofloxacin. Levofloxacin (Levaquin) vs. Lomefloxacin Urinary Tract Infections: Once-daily levofloxacin is as effective as and has a superior tolerability profile than lomefloxacin in the treatment of complicated UTIs Microbiologic eradication rate of pathogens was 95.5% for levofloxacin and 91.7% for lomefloxacin. At the 5 to 9-day posttherapy visit, symptoms were completely resolved in 84.8% of levofloxacin-treated patients and were decreased in 8.2% (93.0% clinical success). Among the lomefloxacin-treated patients, complete resolution was seen in 82.4%, with decreased symptoms in 6.1% (88.5% clinical success). Side effects were reported by 10 (2.6%) and 18 (5.2%) levofloxacin- and lomefloxacin-treated patients, respectively. Compared with levofloxacin-treated patients, more lomefloxacin-treated patients experienced photosensitivity reactions and dizziness. Nausea was more frequent in the levofloxacin-treated group. Six patients in each treatment group had a gastrointestinal side effects (1.7%); rash was reported more frequently with lomefloxacin than with levofloxacin. Discontinuation because of side effects was occured in 8 (3.4%) levofloxacin- and 14 (6.1%) lomefloxacin-treated patients. Acute Pyelonephritis:

14

Product Manual: TOPLEVO Predominant organism was E. coli Eradication rates similar 95%(Le) 95%(Lo) Relapse rates were similar Clinical cure (microbiologic and clinical success) rates 92%(Le) 80%(Lo) Rates of clinical success (cure plus improvement) were similar Adverse events 2%(Le) 5%(Lo) Levofloxacin vs. Clarithromycin Bacterial exacerbation of chronic obstructive pulmonary disease (COPD). In the study levofloxacin and clarithromycin showed similar exacerbation-free intervals. The bacteriological eradication rate was significantly higher with the levofloxacin treatment. Community-acquired pneumonia: Clarithromycin ER has equivalent efficacy and tolerability to the levofloxacin in the treatment of community-acquired pneumonia. Of 299 patients randomized and treated, 252 were clinically evaluable (128 clarithromycin ER, 124 levofloxacin). Clinical cure rates were 88% (113/128) and 86% (107/124), and radiographic success rates were 95% (117/123) and 88% (104/118) for clarithromycin ER and levofloxacin, respectively. Both treatment regimens were effective in resolving and improving clinical signs and symptoms of CAP. Bacteriologic cure rates were 86% (80/93) and 88% (85/97) for clarithromycin ER and levofloxacin, respectively. Acute sinusitis: The study showed that, in the treatment of acute sinusitis, daily levofloxacin therapy is as effective as twice-daily clarithromycin therapy with more complete clearing of symptoms and a more tolerable side-effect profile. The proportion of cured patients was higher in the levofloxacin (40.8%) than in the clarithromycin group (29.0%). Of patients receiving levofloxacin and clarithromycin, 22.5% and 39.3%, respectively, experienced adverse events related or possibly related to the study therapy. Levofloxacin vs. Azithromycin Acute bacterial exacerbations of chronic bronchitis. Standard 5-day course of oral azithromycin was clinically and bacteriologically equivalent to a 7-day course of oral levofloxacin in the treatment of ABECB. Favorable results were demonstrated in 89% of patients receiving azithromycin and in 92% of patients receiving levofloxacin by day 4 of therapy. At day 24 favorable responses were approximately 82% and 86%, respectively. The bacterial eradication rates of respiratory pathogens were 96% for azithromycin and 85% for levofloxacin Community-acquired pneumonia: A single 2 g dose of azithromycin microspheres is at least as effective as a 7-day course of levofloxacin in the treatment of mild to moderate community-acquired pneumonia. The cure rates were 89.7% for azithromycin microspheres and 93.7% for levofloxacin. Bacteriologic success at test of cure in the "bacteriologic per protocol" population was 90.7% for azithromycin microspheres and 92.3% for levofloxacin. Both medications were well tolerated. The incidence of side effects was 19.9% for azithromycin and 12.3% for levofloxacin. Sinusitis: Single 2 g dose azithromycin microspheres has efficacy comparable to 10 days of levofloxacin in the treatment of acute bacterial sinusitis. Clinical success rates were 94.5% 15

Product Manual: TOPLEVO with azithromycin-microspheres and 92.8% with levofloxacin. In patients with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, clinical cure rates were 97.3%, 96.3%, and 100%, respectively, for the azithromycin and 92.3%, 100%), and 90.9%, respectively, for the levofloxacin. Levofloxacin vs. Cefuroxime axetil Acute bacterial exacerbations of chronic bronchitis (ABECB): The clinical response was rated a success, with the patient cured or improved in 94.6% of those receiving levofloxacin and 92.6% of the cefuroxime axetil group. All of the symptoms of bronchitis were resolved in more than 86% of the patients, with the exception of shortness of breath, which resolved in 69.7% of levofloxacin-treated and 72.4% of cefuroxime axetiltreated patients. Community-acquired pneumonia: Levofloxacin is superior to ceftriaxone and/or cefuroxime axetil in the treatment of community-acquired pneumonia Clinical success was higher with levofloxacin treatment (96%) compared with the ceftriaxone and/or cefuroxime axetil (90%). In patients with typical respiratory pathogens the bacteriologic eradication rates were higher with levofloxacin (98%) compared with the ceftriaxone and/or cefuroxime axetil (85%). Levofloxacin eradicated 100% of the most frequently reported respiratory pathogens (i.e., H. influenzae and S. pneumoniae) and provided a >98% clinical success rate in patients with atypical pathogens. Sinusitis: Levofloxacin is more effective than cefuroxime for the treatment of sinusitis. In the study the treatment success rates were 97.4% for patients who received levofloxacin and 92.8% for patients who received cefuroxime. The resolution rates of bacteria were 91.6% and 80.0%, respectively. Levofloxacin vs. Cefdinir Rhinosinusitis: Cefdinir is effective as the levofloxacin in the treatment of acute rhinosinusitis. Clinical cure rate at the test-of-cure visit in the cefdinir group was 83% and in the levofloxacin group 86%. Cefdinir and levofloxacin were comparable in the treatment of moderate to severe infections. The incidence of drug side effects was generally comparable in the 2 treatment groups, although there were significant differences between cefdinir and levofloxacin in the incidence of vaginal moniliasis in women (11% vs 0%), diarrhea (8% vs 1%), and insomnia (0% vs 4%).

16