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Elea S.A.C.I.y A. - Argentina

LEFLUMAX
OVUMIX

Forms and presentation
Leflumax 500 mg: Coated tablets: Box of 7.
Leflumax 750 mg: Coated tablets: Box of 5.

Composition
Leflumax 500 mg: Each tablet contains: Levofloxacin hemihydrate: 500 mg.
Leflumax 750 mg: Each tablet contains: Levofloxacin hemihydrate: 750 mg.
Excipients: crospovidone, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone K30, polyethylene glycol 6000, hydroxypropyl methylcellulose, titanium dioxide, red iron oxide.

Properties
Therapeutic Action: Broad-spectrum antibiotic with action against a wide variety of both aerobic and anaerobic Gram- and Gram+ bacteria. Active against atypical microorganisms, such as C. pneumoniae and M. pneumoniae.
Pharmacodynamics: Levofloxaxin is an antimicrobial agent from the quinolones group. The antibacterial activity of ofloxacin is mainly due to its Levo isomer. The mechanism of action of levofloxacin, as well as other quinolones, involves the inhibition of DNA gyrase (topoisomerase II with bactericidal action), an enzyme required for the replication, transcription, repair, and recombination of DNA. The Levo isomer produces more hydrogen bonds, and therefore more stable complexes with DNA gyrase in the Dextro isomer. Microbiologically, this means an antibacterial activity 25-40 times higher of the Levo isomer-levofloxacin- in comparison with the Dextro isomer. Quinolones rapidly and specifically inhibit the synthesis of bacterial DNA.

Pharmacokinetics
Absorption: Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1-2 hrs after oral dosing. The absolute bioavailability of a 500 mg of Levofloxacin is approximately 99%. No clinically significant effect of the food over Levofloxacin absorption was observed. Therefore, Levofloxacin can be administered regardless to food. Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral dosing regimens. After single doses of 250-1000 mg of Levofloxacin, plasma concentrations increase proportionally to the dose. Steady-state conditions are reached within 48 hrs after administration of 500 mg once or twice a day. Stable Cmax were reached after multiple oral doses once a day were approximately 5.7 and 0.5 µg/ml, respectively; after multiple oral doses administrated twice a day, concentration were approximately 7.8 and 3.0 µg/ml, respectively.
Distribution: The mean volume of distribution of Levofloxacin generally ranges from 89 and 112 liters after single and multiple 500 mg doses, indicating widespread distribution into body tissues over a clinically relevant range (1-10 mg/dl) of serum/plasma Levofloxacin concentrations, Levofloxacin is approximately 24-38% bound to serum proteins across all species studies. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism and elimination: Levofloxacin is stable in plasma and urine and does not invert metabolically to its enantiomer D-floxacin. 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 hrs, whereas less than 4% of the dose was recovered in feces in 72 hrs. 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. The mean terminal plasma elimination half-life of Levofloxacin ranges from approximately 6-8 hrs following single or multiple doses of Levofloxacin. The mean apparent total body clearance and renal clearance range from approximately 144 and 226 ml/min and between 96 and 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 concomitant. Administration of either cimétidine or probénécide results in approximately 24% and 36% reduction in the Levofloxacin renal clearance, respectively, indicating that secretion of Levofloxacin occurs in the renal proximal tubule.

Indications
Infections of superior and inferior respiratory tract, in patients from 18 years old, with mild, moderate, and severe infections caused by susceptible microorganisms: acute maxilar sinusitis due to Str. pneumoniae, H. influenzae or M. catarrhalis; acute bacterial exacerbation of chronic bronchitis due to Staph. aureus, Str. pneumoniae, H. influenzae, H. parainfluenzae or M. catarrhalis; Nosocomial pneumoniae due to Staph. aureus meti-S P. aeruginosa, Serratia marcescens, E. coli, K. pneumoniae, H. influenzae or Str. pneumoniae. Adjunctive therapy should be used as clinically indicated. Where P. aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal (β)-lactam is recommended; community-acquired pneumoniae due to Staph. aureus, Str. pneumoniae (including penicillin-resistant stains, CIM for penicillin not under 2 μg/ml), H. influenzae, H. parainfluenzae, K. pnemoniae, M. catarrhalis, C. pneumoniae, L. pneumophila or M. pneumoniae; complicated skin and mucous infection due to Staph. aureus meti-S, E. faecalis, Str. pyogenes or P. mirabilis; uncomplicated skin and mucous infection (mild to moderate) including abscesses, cellulites, furuncles, impetigo, pyoderma, wound infections, due to Staph. aureus or Str. pyogenes; chronic bacterial prostatitis due to E. coli, E. faecalis or Staph. epidermidis; complicated urinary tract infections (mild to moderate) due to E. faecalis, Enterobacter cloacae, E. coli, K. pneumoniae, P. mirabilis, or P. aeruginosa; acute Pyelonephritis (mild to moderate) caused by E. coli; uncomplicated urinary tract infections (mild to moderate) due to E. coli, K. pneumoniae or Staph. saprophyticus; mild and localized intra-abdominal infections, associated with an effective antibiotic against anaerobics, bacteraemia/septicaemia in patients with pneumonia or infections of urinary tract, not as empirical treatment, as in patients with infections by germes sensitives to Levofloxacin, when other antimocrobials of reduced spectrum are not effective.

Contraindications
Hypersensitivity to Levofloxacin, other quinolones or any excipient of product, epilepsy, history of tendon problems due to administration of fluoroquinolones, children and adolescents, pregnancy and lactation.

Precautions
Use with extreme caution in patients with tendency to convulsive crises (with pre-existing injuries of the CNS) or under concomitant treatment with fenbufen and similar NSAI drugs, or with drugs that reduce the threshold of cerebral convulsive crises (e.g., theophylline).
If pseudomembranous colitis is suspected, suspend therapy and establish suitable treatment. If tendinitis is suspected, suspend the medication immediately and initiate suitable treatment (for example, immobilization). Among patients receiving quinolones, including ciprofloxacin, levofloxacin, ofloxacin, and moxifloxacin, there have been cases of tendon rupture in the shoulder, hand and especially the Achilles tendon, or others requiring surgery or resulting in prolonged incapacity. Post-marketing pharmacovigilance reports indicate that this risk is increased in patients who have received or are receiving corticosteroid therapy, especially in those older than 65 years of age. Product administration should be discontinued if the patient shows symptoms suggestive of tendinitis (pain, inflammation) or tendon rupture. Patients should rest and refrain from exercising until a diagnosis of tendinitis or tendon rupture has been discarded.
Rupture may occur from 48 hrs after treatment initiation with any of the drugs mentioned until after treatment completion. Patients older than 65 years of age are at greater risk of developing severe tendon conditions, including rupture, when treated with any of the quinolones mentioned before. This risk increases in patients who were or are under treatment with corticosteroids. Ruptures usually affect the Achilles tendon, or the tendons in hands or shoulders, and may occur during the antibiotic therapy or several months after treatment completion. Patients should be warned about this adverse effect; drug administration should be discontinued in case of any of these symptoms, and the patient should contact the physician immediately. There have been cases of severe and occasionally fatal hypersensitivity and/or anaphylactic reactions (which may occur after the first dose or after multiple doses); therefore, the medication should be suspended immediately at the first sign and support measures should be instituted. The patient should be adequately hydrated.
Dose adjustment is required for patients with renal failure.
Avoid strong sunlight or artificial UV light exposure.
Prolonged use may result in over infection. Precaution should be warranted in patients with renal failure or with actual or latent glucose-6-phosphate dehydrogenase deficiency. A strict control of diabetic patients concomitantly treated with an oral hypoglycaemic agent or insulin is recommended, since there have been reports of glycemia disorders.
Pediatric use: contraindicated in children and teenagers (younger than 18 years old).

Drug interactions
Theophylline, fenbufen, or similar NSAI drugs. Probenecid and cimetidine. Cyclosporine. Vitamin K antagonists, warfarin. Antidiabetic drugs. Tablet absorption is affected by iron salts, magnesium- or aluminum-containing antacids, and sucralfate. It may cause false negative results in the bacteriological diagnosis of tuberculosis.

Ability to drive and use machine
Precaution is required in handling or use of machines.

Pregnancy and lactation
Contraindicated during pregnancy and lactation.

Side effects
Common: Nausea, diarrhea, increase of hepatic enzyme.
Occasional: Pruritus, rash, anorexia, vomiting, abdominal pain, dyspepsia, headache, dizziness/vertigo, somnolence, insomnia, increased serum bilirubin and creatinine, eosinophilic, leukopenia, asthenia, fungal overgrowth and proliferation of other resistant microorganisms.
Rare: Urticaria, bronchospasm/dyspnea, bloody diarrhea, depression, anxiety, psychotic reactions, paresthesia, fear, agitation, confusion, convulsions, tachycardia, hypotension, arthralgia, myalgia, tendon disorders including tendinitis, neutropenia, thrombocytopenia.
Very rare: Angioedema, hypotension, anaphylactic shock, photosensitization; hypoglycemia, especially in diabetic patients; hypoesthesia, visual and auditive alterations, taste and smelling  perversion; anaphylactic/anaphylactoid shock; tendon rupture (for example, Achilles tendon), muscle weakness (it could be especially important in patients with myasthenia gravis); hepatic reactions such as hepatitis, acute renal failure; agranulocytosis; allergic pneumonitis, fever; extra-pyramidal symptoms and other muscle coordination disorders, vasculitis due to hypersensitivity, porphyria attacks in patients already suffering from this disease.
Isolated cases: Severe bullous eruptions (such as Stevens Johnson's syndrome), toxic epidermal necrolysis (Lyell's syndrome), and multiform exudative erythema, prolongation of the QT interval, rhabdomyolysis, hemolytic anemia, pancytopenia. There were also reports of abnormal EEG, encephalopathy, vasodilation, multi-organic failure, torsades de pointes, increased prothrombin time, and dysphonia.

Dosage and administration
Usual dose for adults is 500-750mg (1 coated tablet) every 24 hrs.
The antibiotic can be administrated in any moment of the day, due to food intake does not interfere with adsorption.

Storage conditions
Keep at no more than 30°C in its original package.

Origin: Argentina
Laboratories: Laboratorio Elea
Distributor: Droguerie Phenicia
Number & Year of Registration
500 mg: 222363/2008
750 mg: 222364/2008