Levocin

Levocin

levofloxacin

Manufacturer:

Getz Pharma

Distributor:

Getz Bros
Full Prescribing Info
Contents
Levofloxacin (IV Infusion: Hemihydrate).
Description
Levofloxacin (Levocin) Tablet 500 mg: Each film-coated tablet contains: Levofloxacin 500mg.
Levofloxacin (Levocin) Tablet 750 mg: Each film-coated tablet contains: Levofloxacin 750mg.
Levofloxacin (Levocin) IV Infusion 500 mg/100mL: Each mL solution for infusion contains: Levofloxacin 5mg (as Hemihydrate).
Levofloxacin (Levocin) IV Infusion 750 mg/150mL: Each mL solution for infusion contains: Levofloxacin 5mg (as Hemihydrate).
Levofloxacin (Levocin) is a synthetic broad-spectrum antibacterial agent. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin with a chemical name of: (-)-(S)-9-fluoro-2, 3-dihydro-3-methyl-10-(4-methyl-piperazinyl)-7-oxo-7H-pyrido-[1,2,3,-de][1,4] benzoxazine-6-carboxylic acid.
The molecular formula is C18H20FN3O4.
Action
Pharmacology: Mechanism of Action: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The main mechanism of action of levofloxacin involves the inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.
Levofloxacin has in vitro activity against the following gram-negative and gram-positive microorganisms. It is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. It is generally considered to be about twice as active as its isomer, ofloxacin.
Pharmacokinetics: FC tablet: Levofloxacin is rapidly and almost completely absorbed following oral use with peak plasma concentrations achieved within 1 hour of a dose. It is distributed into body tissues including the bronchial mucosa and lungs, but penetration into CSF is relatively poor.
Levofloxacin is approximately 30-40% bound to plasma proteins. It is only metabolised to a small degree to inactive metabolites. The elimination half-life of levofloxacin is 6-8 hours, although this may be prolonged in patients with renal impairment. Levofloxacin is excreted largely unchanged, primarily in the urine. It is not removed by hemodialysis or peritoneal dialysis.
Special Population: Renal Insufficiency: Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance <50mL/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 insufficiency: Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin is not expected to be affected by hepatic impairment.
Pediatric: The pharmacokinetics of levofloxacin in pediatric subjects has not been studied.
IV Infusion: Absorption: Following a single intravenous dose of levofloxacin, the mean ±SD peak plasma concentration attained was 6.2±1 μg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 μg/mL after a 750 mg dose infused over 90 minutes.
Levofloxacin IV pharmacokinetics are linear and predictable after single and multiple dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once daily dosage regimens. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4±0.8 and 0.6±0.2 μg/mL after the 500 mg doses 12.1 ± 4.1 and 1.3 ±0.71 μg/mL after the 750 mg doses, respectively.
Distribution:
The mean volume of distribution generally ranges from 74-112 litres after single and multiple dosing of 500 mg or 750 mg dose, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in body fluid of healthy subjects at approximately 3 hours after dosing.
Levofloxacin is approximately 24 to 38% bound to serum proteins. Levofloxacin is mainly bound to serum albumin in humans. The binding of levofloxacin to serum proteins is independent of the drug concentration.
Metabolism and Elimination: Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. 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. The mean terminal elimination half-life (t½) of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin. The mean apparent total body clearance and renal clearance range from approx. 144-226 mL/min and 96-142 mL/min, respectively.
Special Populations: Pediatric Patients: The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposure than adults for a given mg/kg dose, dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC0-24 and Cmax) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.
Renal Insufficiency: 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 Insufficiency: 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.
Microbiology: FC tablet: Levofloxacin has been shown to be active against most strains of the following micro-organisms both in vitro and in clinical infections.
Aerobic Gram-Positive Microorganisms: Enterococcus faecalis (moderately susceptible), Staphylococcus aureus (methicillin-susceptible strains), Staphylococcus epidermidis (methicillin-susceptible strains), Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes.
Aerobic Gram-Negative Microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Salmonella species, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa (some strains of Pseudomonas aeruginosa may develop resistance rapidly during treatment with levofloxacin), Serratia marcescens.
Anaerobic Microorganisms: Bacteroides fragilis, Clostridium perfringens, Peptostreptococcus.
Other Microorganisms: Chlamydia pneumoniae, Mycoplasma pneumoniae.
IV Infusion: Commonly susceptible species: Aerobic Gram-Positive Microorganisms: Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptoccus pneumoniae, Streptococcus pyogenes.
Aerobic Gram-Negative Microorganisms: Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.
Anaerobic Microorganisms: Peptostreptococcus.
Other: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.
Species for which acquired resistance may be a problem: Aerobic Gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant, Coagulase negative Staphylococcus spp.
Aerobic Gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.
Anaerobic bacteria: Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotamicron, Bacteroides vulgatus, Clostridium difficile.
Levofloxacin has been shown to be active against Bacillus anthracis in vitro.
Indications/Uses
Levofloxacin (Levocin) is indicated for 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 as follows: Acute bacterial sinusitis, Acute bacterial exacerbation of chronic bronchitis, Community-acquired pneumonia and nosocomial pneumonia, Typhoid & paratyphoid fever.
FC tablet: Acute maxillary sinusitis, Complicated skin and skin structure infections.
IV infusion: Uncomplicated skin and soft tissue infections, Complicated skin and soft tissue infections, Chronic bacterial prostatitis, Complicated urinary tract infections, Uncomplicated urinary tract infections, Acute pyelonephritis, Inhalation anthrax (post-exposure).
Dosage/Direction for Use
FC tablet: Levofloxacin (Levocin) tablets are administered once or twice daily. The dosage depends on the types and severity of the infections and the sensitivity of the presumed, causative pathogen.
Levofloxacin (Levocin) should be swallowed without crushing and with sufficient amount of liquid. The tablets may be taken during meals or between meals.
Levofloxacin (Levocin) tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc.
The dosage guidelines as per the infection are given as follows. (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

IV infusion: Levofloxacin (Levocin) I.V. Infusion is indicated when intravenous administration offers a route of administration advantageous to the patient. Rapid or bolus intravenous infusion must be avoided. The usual dose of Levofloxacin (Levocin) I.V. Infusion is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours. The dosage depends on the types and severity of the infections and the sensitivity of the presumed causative pathogen. Levofloxacin (Levocin) I.V. Infusion should not be mixed with heparin or alkaline solutions (e.g., sodium hydrogen carbonate).
The dosage guidelines as per the infection are given as follows. (See Tables 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image
Overdosage
Levofloxacin exhibits a low potential for acute toxicity. 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.
Contraindications
Levofloxacin is contraindicated in patients with a history or known hypersensitivity to this drug and/or other fluoroquinolone antibacterials.
FC tablet: Levofloxacin is not indicated for pediatric patients (less than 18 years of age). An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) has been observed in these patients.
IV infusion: Patients with epilepsy; history of tendon disorders related to fluoroquinolone administration.
Special Precautions
FC tablet: Although levofloxacin is more soluble than other quinolones, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine.
As with other quinolones, 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).
Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving drugs in this class. Excessive exposure to sunlight should be avoided. Therapy should be discontinued if phototoxicity (skin eruptions) occurs.
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, including levofloxacin. Levofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted.
Levofloxacin should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including levofloxacin.
As with any potent antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during therapy.
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. If 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.
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.
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.
As with other quinolones, disturbances of blood glucose, including symptomatic hyper and hypoglycemia, have been reported with levofloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. 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.
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.
An increased rate of aortic aneurysm and dissection has been reported within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve Levofloxacin for use only when there are no alternative antibacterial treatments available.
IV infusion: General: No fluoroquinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous.
Infusion Time: The recommended infusion time of at least 30 minutes for 250 mg, 60 minutes for 500 mg or 90 minutes for 750 mg Levofloxacin solution for infusion should be observed. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of levofloxacin, the infusion must be halted immediately.
Tendinitis and tendon rupture: Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in patients using corticosteroids. Close monitoring of these patients is therefore necessary if they are prescribed levofloxacin. All patients should consult their physician if they experience symptoms of tendinitis.
Clostridium difficile-associated disease: Diarrhea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin solution for infusion, may be symptomatic of Clostridium difficile associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin solution for infusion must be stopped immediately and patients should be treated with supportive measures with specific therapy without delay.
Patients predisposed to seizures: Quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients with pre-existing central nervous system lesions, concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline.
Patients with G-6-phosphate dehydrogenase deficiency: Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibacterial agents, and so levofloxacin should be used with caution.
Patients with renal impairment: Since Levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin should be adjusted in patients with renal impairment.
Hypoglycemia: As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent or with insulin. In these diabetic patients, careful monitoring of blood glucose is recommended.
Prevention of photosensitisation: Although photosensitisation is very rare with levofloxacin, it is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g., sunray lamp, solarium), in order to prevent photosensitisation.
Patients treated with Vitamin K antagonists: Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation tests should be monitored when these drugs are given concomitantly.
Psychotic reactions: Caution is recommended if levofloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.
QT interval prolongation: Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example: congenital long QT syndrome; concomitant use of drugs that are known to prolong the QT interval (e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides); uncorrected electrolyte imbalance (e.g., hypokalemia,hypomagnesemia); elderly; cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).
Peripheral neuropathy: Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.
Opiates: In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.
Hepatobiliary disorders: Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Risk of Aortic Aneurysm and Dissection: An increased rate of aortic aneurysm and dissection has been reported within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve Levofloxacin for use only when there are no alternative antibacterial treatments available.
Renal insufficiency: FC tablet/ IV infusion: Levofloxacin should be administered with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. In patients with impaired renal function (creatinine clearance<50 mL/min), adjustment of dose regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance.
Use in Pregnancy: Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
FC tablet: There are no adequate and well-controlled studies in pregnant women.
IV infusion: The safety and efficacy of levofloxacin in pregnant women has not been established.
Use in Lactation: FC tablet/IV infusion: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, 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, nursing should not be undertaken by mothers who must use levofloxacin.
Use In Pregnancy & Lactation
Pregnancy: Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
FC tablet: There are no adequate and well-controlled studies in pregnant women.
IV infusion: The safety and efficacy of levofloxacin in pregnant women has not been established.
Nursing Mothers: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, 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, nursing should not be undertaken by mothers.
Adverse Reactions
Levofloxacin is usually well tolerated. However, following are the adverse effects reported during its therapy.
Common: Moniliasis, insomnia, headache, dizziness, dyspnea, nausea, diarrhea, constipation, abdominal pain, vomiting, dyspepsia, rash, pruritus, vaginitis, edema, chest pain.
Less Common: Genital moniliasis, anemia, thrombocytopenia, granulocytopenia, allergic reaction, hyperglycemia, hypoglycemia, hyperkalemia, anxiety, agitation, confusion, depression, hallucination, nightmare, sleep disorder, anorexia, abnormal dreaming, tremor, convulsions, paresthesia, vertigo, hypertonia, hyperkinesias, abnormal gait, somnolence, syncope, epistaxis, cardiac arrest, palpitation, ventricular tachycardia, ventricular arrhythmia, phlebitis, gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, glossitis, pseudomembranous/C. difficile colitis, abnormal hepatic function, increased hepatic enzymes, increased alkaline phosphatase, urticaria, arthralgia, tendonitis, myalgia, skeletal pain, abnormal renal function, acute renal failure.
Drug Interactions
Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concomitant administration of NSAIDs with a quinolone, including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures.
Antidiabetic Agents: Disturbances of blood glucose, including hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and an antidiabetic agent (e.g., glyburide/glibenclamide) or insulin. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered.
FC tablet: Antacids, Sucralfate, Metal Cations, Multivitamins: 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. These agents should be taken at least 2 hours before or 2 hours after levofloxacin administration.
Theophylline, Cyclosporine, Digoxin, Probenecid and Cimetidine: No significant effect of levofloxacin on the plasma concentrations, AUC and other disposition parameters for theophylline, cyclosporine, digoxin, probenecid and cimetidine was detected in a clinical study.
Warfarin: There have been no reports during the post marketing experience in patients that levofloxacin enhances the effects of warfarin. Prothrombin time, International Normalized Ratio (INR) or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.
IV infusion: Multivalent cations: No quinolone should be co-administered with any solution containing multivalent cations, e.g. magnesium, through the same intravenous line.
Storage
Store at temperatures not exceeding 30°C.
FC tablet: Protect from sunlight and moisture.
IV Infusion: Do not refrigerate.
Protect from light.
Keep in the pack until required.
Once the vial is removed from the carton, the infusion solution must be used within three days.
Once the vial has been opened, the infusion solution must be used within three hrs.
MIMS Class
Quinolones
ATC Classification
J01MA12 - levofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.
Presentation/Packing
FC tab 500 mg x 10's. 750 mg x 10's. IV infusion 500 mg x 1's. 750 mg x 1's.
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