Indications and Clinical UseSafety and effectiveness in children under 18 years of age have not been established (see Warnings and Precautions, Special Populations). Acute sinusitis (mild to moderate) due to S. pneumoniae, H. influenzae, or M. (Branhamella) catarrhalis. Uncomplicated skin and skin structure infections (mild to moderate) due to S. aureus or S. pyogenes. Complicated skin and skin structure infections (mild to moderate), excluding burns, due to E. faecalis, methicillin-sensitive S. aureus, S. pyogenes, P. mirabilis, or S. agalactiae. Complicated urinary tract infections (mild to moderate) due to E. (Streptococcus) faecalis, E. cloacae, E. coli, K. pneumoniae, P. mirabilis, or P. aeruginosa (see Dosage and Administration). Uncomplicated urinary tract infections (mild to moderate) due to E. coli, K. pneumoniae, or S. saprophyticus. Acute pyelonephritis (mild to moderate) caused by E. coli (see Dosage and Administration). Chronic bacterial prostatitis due to E. coli, E. faecalis, or S. epidermidis. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify the organisms causing the infection, and to determine their susceptibility to levofloxacin. Therapy with levofloxacin may be initiated before the results of these tests are known; once results become available, appropriate therapy should be continued. As with other drugs in this class, some strains of P. aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin. Culture and susceptibility testing performed periodically during therapy, will reveal not only the therapeutic effect of the antimicrobial agent, but also the possible emergence of bacterial resistance. Acute bacterial exacerbations of chronic bronchitis (mild to moderate) due to S. aureus, S. pneumoniae, H. influenzae, H. parainfluenzae, or M. (Branhamella) catarrhalis. Community-acquired pneumonia (mild, moderate and severe infections) due to S. aureus, S. pneumoniae (including penicillin-resistant strains), H. influenzae, H. parainfluenzae, K. pneumoniae, M. (Branhamella) catarrhalis, C. pneumoniae, L. pneumophila, or M. pneumoniae (see Dosage and Administration). Nosocomial pneumonia due to methicillin-susceptible S. aureus, P. aeruginosa, S. marcescens, E. coli, K. pneumoniae, H. influenzae or S. 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. Drug absorption appears to be unaffected by age. Dose adjustment based on age alone is not necessary (see Warnings and Precautions, Special Populations and Action and Clinical Pharmacology).
OverdosageFor management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed, including ECG monitoring (see Action and Clinical Pharmacology, Pharmacodynamics, Studies Measuring Effects on QT and Corrected QT (QTc) Intervals), and appropriate hydration maintained. Treatment should be supportive. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic levofloxacin exposure.
LEVAQUIN exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of LEVAQUIN: 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. Dosage Forms, Composition and PackagingEach modified rectangular, film-coated, white tablet, embossed “LEVAQUIN” on one side and “750” on the other, contains: levofloxacin 750 mg. Nonmedicinal ingredients: crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Bottles of 50. Each modified rectangular, film-coated, peach tablet, embossed “LEVAQUIN” on one side and “500” on the other, contains: levofloxacin 500 mg. Nonmedicinal ingredients: crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, synthetic red and yellow iron oxides and titanium dioxide. Bottles of 50. Each modified rectangular, film-coated, terra cotta pink tablet, embossed “LEVAQUIN” on one side and “250” on the other, contains: levofloxacin 250 mg. Nonmedicinal ingredients: crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, synthetic red iron oxide and titanium dioxide. Bottles of 50. Each mL of sterile, non-pyrogenic, premixed, ready-to-use solution contains: levofloxacin 5 mg in 5% Dextrose (D5W). pH: 3.8 to 5.8. Solutions of hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH. Preservative-free. The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyester (CR3). The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container's chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers. Single-use flexible containers of 100 mL with a fill volume of 50 or 100 mL, 150 mL with a fill volume of 150 mL, cases of 12.
Warnings and PrecautionsSafety and efficacy of levofloxacin in patients with impaired renal function (creatinine clearance ≤80 mL/min) have not been studied. Since levofloxacin is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The potential effects of levofloxacin associated with possible increased serum/tissue levels in renal impaired patients, such as effect on QTc interval, have not been studied. Adjustment of the dosage regimen may be necessary to avoid the accumulation of levofloxacin due to decreased clearance. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy, since elimination of levofloxacin may be reduced. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Administer levofloxacin with caution in the presence of renal insufficiency (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function). Because rapid or bolus intravenous injection may result in hypotension, levofloxacin injection should only be administered by slow intravenous infusion over a period of 60 minutes for a 500 mg dose, and 90 minutes for a 750 mg dose (see Dosage and Administration). Some quinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. During post-marketing surveillance, very rare cases of torsades de pointes have been reported in patients taking levofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. The risk of arrhythmias may be reduced by avoiding concurrent use with other drugs that prolong the QT interval including macrolide antibiotics, antipsychotics, tricyclic antidepressants, Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic agents, and cisapride. In addition, use of levofloxacin in the presence of risk factors for torsades de pointes such as hypokalemia, significant bradycardia, cardiomyopathy, patients with myocardial ischemia, and patients with congenital prolongation of the QT interval should be avoided. Ruptures of the shoulder, hand, Achilles tendon, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including levofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. 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 (see Contraindications). Convulsions and toxic psychoses have been reported in patients receiving quinolones, including levofloxacin. Quinolones including levofloxacin, may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, dizziness, confusion and hallucinations, paranoia, depression, nightmares, insomnia and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving levofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, levofloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. alcohol abuse, certain drug therapies such as NSAIDs and theophylline, renal dysfunction). Levofloxacin should be used with caution in patients with unstable psychiatric illness (see Drug Interactions, and Adverse Reactions). 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 levofloxacin. 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. The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. It may also be useful to monitor renal function. Elderly patients may be more susceptible to drug-associated effects on the QT interval (see Warnings and Precautions, Cardiovascular). There are 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. Very rare post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7000 patients. 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. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis (see Adverse Reactions, Post-Market Adverse Drug Reactions). The safety and efficacy of LEVAQUIN levofloxacin tablets and injection in children, adolescents (under the age of 18 years), pregnant women, and nursing mothers have not been established. Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, 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. 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 (see Adverse Reactions). Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have rarely been reported in patients receiving therapy with quinolones, including levofloxacin. These events may be severe, and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever; rash or severe dermatologic reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis, including acute hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The administration of levofloxacin should be discontinued immediately, at the first appearance of a skin rash or any other sign of hypersensitivity, and supportive measures instituted (see Adverse Reactions). Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight or ultraviolet (UV) light while receiving drugs in this class. Excessive exposure to sunlight or UV light should be avoided. However, in clinical trials with levofloxacin, phototoxicity has been observed in less than 0.1% of patients. Therapy should be discontinued if phototoxicity (e.g. skin eruption) occurs. The oral and intravenous administration of levofloxacin increased the incidence and severity of osteochondrosis in immature rats and dogs. Other quinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species. Consequently, levofloxacin should not be used in pre-pubertal patients. Although levofloxacin is soluble, adequate hydration of patients receiving LEVAQUIN levofloxacin should be maintained to prevent the formation of a highly concentrated urine. Crystalluria has been observed rarely in patients receiving other quinolones, when associated with high doses and an alkaline urine. Although crystalluria was not observed in clinical trials with levofloxacin, patients are encouraged to remain adequately hydrated. As with any antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy (see Adverse Reactions). Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with the use of quinolones, including LEVAQUIN. In patients treated with LEVAQUIN, some of these cases were serious. Blood glucose disturbances were usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g. glyburide/glibenclamide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, discontinue levofloxacin immediately and initiate appropriate therapy (see Drug Interactions, and Adverse Reactions). Serious hypoglycaemia and hyperglycemia have also occurred in patients without a history of diabetes. Levofloxacin is not indicated for the treatment of syphilis or gonorrhea. Levofloxacin is not effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with antimicrobial agents with limited or no activity against T. pallidum should have a follow-up serologic test for syphilis after 3 months. Levofloxacin is not indicated for the treatment of patients younger than 18 years of age. Quinolones, including levofloxacin, cause arthropathy in juvenile animals of several species. The incidence of protocol-defined musculoskeletal disorders in a prospective long-term surveillance study was higher in children treated for approximately 10 days with levofloxacin than in children treated with non-fluoroquinolone antibiotics for approximately 10 days (see Adverse Reactions). Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin can 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. C. difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including levofloxacin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against C. difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases (see Adverse Reactions).
Storage and StabilityLEVAQUIN Tablets should be stored at controlled room temperature (15-30°C) in well-closed containers. When stored under recommended conditions, LEVAQUIN Injection, as supplied in flexible containers, is stable through the expiration date printed on the label. LEVAQUIN Injection PREMIX in flexible containers should be stored at 2-25°C; however, brief exposure up to 40°C does not adversely affect the product. Avoid excessive heat and protect from freezing and light. Store with protective overwrap and use immediately once removed from the overwrap.
Action and Clinical PharmacologyThe mean volume of distribution of levofloxacin generally 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 (11.7 µg/g for a 750 mg dose) and in blister fluid (4.33 µg/g for a 500 mg dose) at approximately 3-4 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2. The blister fluid to plasma AUC ratio is approximately 1, following multiple once-daily oral administration of 750 mg and 500 mg levofloxacin to healthy subjects, respectively. Levofloxacin also penetrates 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 µg/g over a 24-hour period after a single 500 mg oral dose. Levofloxacin is 24 to 38% bound to serum proteins across all species studied. Levofloxacin binding to serum proteins is independent of the drug concentration. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean peak plasma concentration attained was 6.2 µg/mL after a 500 mg dose infused over 60 minutes, and 7.99 µg/mL after a 750 mg dose infused over 90 minutes. Levofloxacin pharmacokinetics are linear and predictable after single and multiple i.v. dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosing regimen. The peak and trough plasma concentrations attained following multiple once-daily i.v. regimens were approximately 6.4 µg/mL and 0.6 µg/mL after the 500 mg doses, and 7.92 µg/mL and 0.85 µg/mL after the 750 mg doses, respectively. The plasma concentration profile of levofloxacin after i.v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i.v. routes of administration can be considered interchangeable (see Figure 1). The major route of elimination of levofloxacin in humans is 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 or intravenously.
| Regimen | N | Cmax
(µg/mL) | Tmax
(h) | AUCk
(µg·h/mL) | CL/F
(mL/min) | Vd/F
(L) | t1/2
(h) | Clr
(mL/min) | | Single Dose | | 250 mg p.o.a | 15 | 2.8±0.4 | 1.6±1.0 | 27.2±3.9 | 156±20 | ND | 7.3±0.9 | 142±21 | | 500 mg p.o.a , n | 23 | 5.1±0.8 | 1.3±0.6 | 47.9±6.8 | 178±28 | ND | 6.3±0.6 | 103±30 | | 500 mg i.v.a | 23 | 6.2±1.0 | 1.0±0.1 | 48.3±5.4 | 175±20 | 90±11 | 6.4±0.7 | 112±25 | | 750 mg p.o.d | 10 | 7.1±1.4 | 1.9±0.7 | 82.2±14.3 | 157±28 | 90±14 | 7.7±1.3 | 118±28 | | 750 mg i.v.c | 4 | 7.99±1.2b | ND | 74.4±8.0 | 170±19 | 97.0±14.8 | 7.5±1.9 | ND | | Multiple Dose | | 500 mg q24h p.o.a | 10 | 5.7±1.4 | 1.1±0.4 | 47.5±6.7m | 175±25 | 102±22 | 7.6±1.6 | 116±31 | | 500 mg q24h i.v.a | 10 | 6.4±0.8 | ND | 54.6±11.1m | 158±29 | 91±12 | 7.0±0.8 | 99±28 | | 500 mg or 250 mg q24h i.v. patients with bacterial infectionse | 272 | 8.7±4.0j | ND | 72.5±51.2j , m | 154±72 | 111±58 | ND | ND | | 750 mg q24h p.od | 10 | 8.6±1.9 | 1.4±0.5 | 90.7±17.6 | 143±29 | 100±16 | 8.8±1.5 | 116±28 | | 750 mg q24h i.v.c | 4 | 7.92±0.91b | ND | 72.5±0.8m | 172±2 | 111±12 | 8.1±2.1 | ND | | 500 mg p.o. Single Dose, Effects of Gender and Age | | Malef | 12 | 5.5±1.1 | 1.2±0.4 | 54.4±18.9 | 166±44 | 89±13 | 7.5±2.1 | 126±38 | | Femaleg | 12 | 7.0±1.6 | 1.7±0.5 | 67.7±24.2 | 136±44 | 62±16 | 6.1±0.8 | 106±40 | | Youngh | 12 | 5.5±1.0 | 1.5±0.6 | 47.5±9.8 | 182±35 | 83±18 | 6.0±0.9 | 140±33 | | Elderlyi | 12 | 7.0±1.6 | 1.4±0.5 | 74.7±23.3 | 121±33 | 67±19 | 7.6±2.0 | 91±29 | | 500 mg p.o. Single Dose, Patients with Renal Insufficiency | | ClCr 50–80 mL/min | 3 | 7.5±1.8 | 1.5±0.5 | 95.6±11.8 | 88±10 | ND | 9.1±0.9 | 57±8 | | ClCr 20–49 mL/min | 8 | 7.1±3.1 | 2.1±1.3 | 182.1±62.6 | 51±19 | ND | 27±10 | 26±13 | | ClCr <20 mL/min | 6 | 8.2±2.6 | 1.1±1.0 | 263.5±72.5 | 33±8 | ND | 35±5 | 13±3 | | Hemodialysis | 4 | 5.7±1.0 | 2.8±2.2 | ND | ND | ND | 76±42 | ND | | CAPD | 4 | 6.9±2.3 | 1.4±1.1 | ND | ND | ND | 51±24 | ND | | 750 mg i.v. Single Dose and Multiple Dose, Patients with Renal Insufficiency | | Single dose—ClCr 50–80 mL/minl | 8 | 13.3±3.6 | ND | 128±37 | 104±25 | 62.7±15.1 | 7.5±1.5 | ND | | Multiple q24h dose—ClCr 50–80 mL/minl | 8 | 14.3±3.2 | ND | 145±36 | 103±20 | 64.2±16.9 | 7.8±2.0 | ND | a. Healthy males 18–53 years of age. b. 60 min. infusion for 250 mg and 500 mg doses, 90 min. infusion for 750 mg dose. c. Healthy male subjects 32–46 years of age. d. Healthy male subjects 19–51 years of age. e. Including 500 mg q48h for 8 patients with moderate renal impairment (Cl Cr 20–50 mL/min) and infections of the respiratory tract or skin. f. Healthy males 22–75 years of age. g. Healthy females 18–80 years of age. h. Young healthy male and female subjects 18–36 years of age. i. Healthy elderly male and female subjects 66–80 years of age. j. Dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modelling. k. AUC for 0-∞ reported, unless otherwise specified. l. Male and female subjects 34–54 years of age. m. AUC 0-24 h. n. Absolute bioavailability; F=0.99±0.08 from a 500 mg tablet and F=0.99±0.06 from a 750 mg tablet. Legend: ND=not determined.
There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when the differences in creatinine clearance are taken into consideration. Dose adjustment based on gender alone is not necessary. 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 (87%) in the urine within 48 hours. The pharmacokinetics of levofloxacin in patients with community-acquired bacterial infections are comparable to those observed in healthy subjects. The pharmacokinetics of levofloxacin in pediatric patients have not been studied. 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. There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects’ differences in creatinine clearance are taken into consideration. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary. LEVAQUIN levofloxacin is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration. Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antibacterial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other quinolone antibacterials involves inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Topoisomerases are essential in controlling the topological state of DNA, and are vital for DNA replication, transcription, repair and recombination. Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from other classes of antimicrobial agents, such as β-lactam antibiotics, aminoglycosides, and macrolides. Therefore, microorganisms resistant to these latter classes of antimicrobial agents may be susceptible to fluoroquinolones. For example, β-lactamase production and alterations in penicillin-binding proteins have no effect on levofloxacin activity. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to other classes of antimicrobial agents. The apparent total body clearance and apparent volume of distribution were not affected by race in a covariate analysis performed on data from 72 subjects. Pharmacokinetic parameters of levofloxacin following oral or intravenous doses of levofloxacin in patients with impaired renal function (creatinine clearance ≤80 mL/min) are presented in Table 7. Clearance of levofloxacin is reduced and plasma elimination half-life is prolonged in this patient population. Dosage adjustment may be required in such patients to avoid accumulation. A dosage reduction is being recommended depending on the levels of renal insufficiency. Dosing recommendations are based on pharmacokinetic modeling of data collected from a clinical safety and pharmacokinetic study in renally impaired patients treated with a single 500 mg oral dose of levofloxacin (see Warnings and Precautions, Renal, and Dosage and Administration, Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function). Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating supplemental doses of levofloxacin are not required following hemodialysis or CAPD. Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1 to 2 hours after oral dosing. The absolute bioavailability of a 500 mg tablet and a 750 mg tablet of levofloxacin is approximately 99% in both cases, demonstrating complete oral absorption of levofloxacin. Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 µg/mL and 0.5 µg/mL after the 500 mg doses, and 8.6 µg/mL and 1.1 µg/mL after the 750 mg doses, respectively. There was no clinically significant effect of food on the extent of absorption of levofloxacin. Oral administration with food slightly prolongs the time to peak concentration by approximately 1 hour, and slightly decreases the peak concentration by approximately 14%. Therefore, levofloxacin can be administered without regard to food. Two studies have been conducted to assess specifically the effect of levofloxacin on QT and corrected QT (QTc) intervals in healthy adult volunteers. In a dose escalation study (n=48) where the effect on average QTc, after single doses of 500, 1000, and 1500 mg of levofloxacin, was measured between the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) and the average post-dose QTc interval (calculated from measurements taken every half hour for two hours and at 4, 8, 12 and 24 hours after treatment), an effect on the average QTc (Bazett) was –1.84, 1.55 and 6.40 msec, respectively. In a study which compared the effect of 3 antimicrobials (n=48) where the difference was measured between the baseline QTc (calculated as the average QTc measured 24, 20, 16 hours and immediately before treatment) and the average post-dose QTc interval (calculated from measurements taken every half hour for four hours and at 8, 12 and 24 hours after treatment), an effect on the average QTc was an increase of 3.58 msec after the 1000 mg dose of levofloxacin. The mean increase compared to baseline of QTc at Cmax in these two trials was 7.82 msec and 5.32 msec after a single 1000 mg dose. In these trials, no effect on QT intervals compared to placebo was evident at any of the doses studied. The clinical relevance of the results of these studies is not known.
ContraindicationsLEVAQUIN levofloxacin Tablets and Injection are contraindicated in persons with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product. For a complete listing, see the Dosage Forms, Composition and Packaging.
Levofloxacin is also contraindicated in persons with a history of tendinitis or tendon rupture associated with the use of any member of the quinolone group of antimicrobial agents.
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