- levofloxacin tablet, film coated
Lake Erie Medical DBA Quality Care Products LLC
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LEVAQUIN safely and effectively. See full prescribing information for LEVAQUIN.
LEVAQUIN (levofloxacin) Tablet, Film Coated for Oral use
LEVAQUIN (levofloxacin) Solution for Oral use
LEVAQUIN (levofloxacin) Injection, Solution, Concentrate for Intravenous use
LEVAQUIN (levofloxacin) Injection, Solution for Intravenous use
Initial U.S. Approval: 1996
|Warnings and Precautions|
|Type of Infection||Dose Every 24 hours||Duration
|Nosocomial Pneumonia (1.1)||750 mg||7–14|
|Community Acquired Pneumonia (1.2)||500 mg||7–14|
|Community Acquired Pneumonia (1.3)||750 mg||5|
|Acute Bacterial Sinusitis (1.4)||750 mg||5|
|Acute Bacterial Exacerbation of Chronic Bronchitis (1.5)||500 mg||7|
|Complicated Skin and Skin Structure Infections (SSSI) (1.6)||750 mg||7–14|
|Uncomplicated SSSI (1.7)||500 mg||7–10|
|Chronic Bacterial Prostatitis (1.8)||500 mg||28|
|Complicated Urinary Tract Infection (1.9) or Acute Pyelonephritis (1.11)||750 mg||5|
|Complicated Urinary Tract Infection (1.10) or Acute Pyelonephritis (1.11)||250 mg||10|
|Uncomplicated Urinary Tract Infection (1.12)||250 mg||3|
|Inhalational Anthrax (Post-Exposure) (1.13)|
|Adults and Pediatric Patients > 50 kg and ≥ 6 months of age||500 mg||60|
|Pediatric Patients < 50 kg and ≥ 6 months of age||8 mg/kg BID (not to exceed 250 mg/dose)||60|
|Tablets||250 mg, 500 mg, and 750 mg|
|Oral Solution||25 mg/mL|
|Injection: single-use vials for dilution||500 mg in 20 mL
750 mg in 30 mL
|Injection: premix single-use flexible containers||250 mg in 50 mL
500 mg in 100 mL
750 mg in 150 mL
The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness (6.2).
To report SUSPECTED ADVERSE REACTIONS, contact Ortho-McNeil-Janssen Scientific Affairs Customer Communications Center at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
|Multivalent cation-containing products including antacids, metal cations or didanosine||Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)|
|Warfarin||Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)|
|Antidiabetic agents||Carefully monitor blood glucose (5.10, 7.3)|
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
To reduce the development of drug-resistant bacteria and maintain the effectiveness of LEVAQUIN® and other antibacterial drugs, LEVAQUIN® should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
LEVAQUIN® Tablets/Injection and Oral Solution are 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. LEVAQUIN® Injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form).
Culture and susceptibility testing
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Clinical Pharmacology (12.4)]. Therapy with LEVAQUIN® may be initiated before results of these tests are known; once results become available, appropriate therapy should be selected.
As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with LEVAQUIN®. Culture and susceptibility testing performed periodically during therapy will provide information about the continued susceptibility of the pathogens to the antimicrobial agent and also the possible emergence of bacterial resistance.
LEVAQUIN® is indicated for the treatment of 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 β-lactam is recommended [see Clinical Studies (14.1)].
LEVAQUIN® is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.2)].
MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
LEVAQUIN® is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.3)].
LEVAQUIN® is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].
LEVAQUIN® is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
LEVAQUIN® is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5)].
LEVAQUIN® is indicated for the treatment of 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.
LEVAQUIN® is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6)].
LEVAQUIN® is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7)].
LEVAQUIN® is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)].
LEVAQUIN® is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.
LEVAQUIN® is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of LEVAQUIN® is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of LEVAQUIN® in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged LEVAQUIN® therapy should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1), (2.2) and Clinical Studies (14.9)].
The usual dose of LEVAQUIN® Tablets or Oral Solution is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. The usual dose of LEVAQUIN® Injection 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, 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 [see Dosage and Administration (2.3)].
|Type of Infection*||Dosed Every 24 hours||Duration (days)†|
|Nosocomial Pneumonia||750 mg||7–14|
|Community Acquired Pneumonia‡||500 mg||7–14|
|Community Acquired Pneumonia§||750 mg||5|
|Acute Bacterial Sinusitis||750 mg||5|
|Acute Bacterial Exacerbation of Chronic Bronchitis||500 mg||7|
|Complicated Skin and Skin Structure Infections (SSSI)||750 mg||7–14|
|Uncomplicated SSSI||500 mg||7–10|
|Chronic Bacterial Prostatitis||500 mg||28|
|Complicated Urinary Tract Infection (cUTI) or |
Acute Pyelonephritis (AP)¶
|Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)#||250 mg||10|
|Uncomplicated Urinary Tract Infection||250 mg||3|
| Inhalational Anthrax (Post-Exposure), adult and |
pediatric patients > 50 kg and ≥ 6 months of ageÞ,ß
Pediatric patients < 50 kg and ≥ 6 months of ageÞ,ß
see Table 2 below (2.2)
The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.
|Type of Infection*||Dose||Freq. Once every||Duration†|
|Inhalational Anthrax (post-exposure)‡,§|
|Pediatric patients > 50 kg and ≥ 6 months of age||500 mg||24 hr||60 days§|
|Pediatric patients < 50 kg and ≥ 6 months of age||8 mg/kg|
(not to exceed 250 mg per dose)
|12 hr||60 days§|
Administer LEVAQUIN® 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.
No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min.
In patients with impaired renal function (creatinine clearance <50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)].
Table 3 shows how to adjust dose based on creatinine clearance.
|Dosage in Normal Renal Function Every 24 hours||Creatinine Clearance|
20 to 49 mL/min
10 to 19 mL/min
|Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)|
|750 mg||750 mg every 48 hours||750 mg initial dose, then 500 mg every 48 hours||750 mg initial dose, then 500 mg every 48 hours|
|500 mg||500 mg initial dose, then 250 mg every 24 hours||500 mg initial dose, then 250 mg every 48 hours||500 mg initial dose, then 250 mg every 48 hours|
|250 mg||No dosage adjustment required||250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required||No information on dosing adjustment is available|
LEVAQUIN® Tablets and Oral Solution
LEVAQUIN® Tablets and Oral Solution 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 or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Patient Counseling Information (17.2)].
LEVAQUIN® Injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.6)].
Food and LEVAQUIN® Tablets and Oral Solution
LEVAQUIN® Tablets can be administered without regard to food. It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before or 2 hours after eating.
Caution: Rapid or bolus intravenous infusion of LEVAQUIN® has been associated with hypotension and must be avoided. LEVAQUIN® Injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. LEVAQUIN® Injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.
Hydration for Patients Receiving LEVAQUIN® Tablets, Oral Solution, and Injection
Adequate hydration of patients receiving oral or intravenous LEVAQUIN® should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Because only limited data are available on the compatibility of LEVAQUIN® Injection with other intravenous substances, additives or other medications should not be added to LEVAQUIN® Injection Premix in Single-Use Flexible Containers and LEVAQUIN® Injection in Single-Use Vials, or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of LEVAQUIN® Injection with an infusion solution compatible with LEVAQUIN® Injection and with any other drug(s) administered via this common line
LEVAQUIN® Injection in Single-Use Vials
Single-use vials require dilution prior to administration.
LEVAQUIN® Injection is supplied in single-use vials containing a concentrated levofloxacin solution with the equivalent of 500 mg (20 mL vial) and 750 mg (30 mL vial) of levofloxacin in Water for Injection, USP. The 20 mL and 30 mL vials each contain 25 mg of levofloxacin/mL. These LEVAQUIN® Injection single-use vials must be further diluted with an appropriate solution prior to intravenous administration [see Table 4]. The concentration of the resulting diluted solution should be 5 mg/mL prior to administration.
Compatible Intravenous Solutions: Any of the following intravenous solutions may be used to prepare a 5 mg/mL levofloxacin solution with the approximate pH values:
|Intravenous Fluids||Final pH of LEVAQUIN® Solution|
|0.9% Sodium Chloride Injection, USP||4.71|
|5% Dextrose Injection, USP||4.58|
|5% Dextrose/0.9% NaCl Injection||4.62|
|5% Dextrose in Lactated Ringers||4.92|
|Plasma-Lyte® 56/5% Dextrose Injection||5.03|
|5% Dextrose, 0.45% Sodium Chloride, and 0.15% Potassium Chloride Injection||4.61|
|Sodium Lactate Injection (M/6)||5.54|
Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final intravenous solution. Since the vials are for single-use only, any unused portion remaining in the vial should be discarded. When used to prepare two 250 mg doses from the 20 mL vial containing 500 mg of levofloxacin, the full content of the vial should be withdrawn at once using a single-entry procedure, and a second dose should be prepared and stored for subsequent use [see Stability of LEVAQUIN® Injection Following Dilution].
Prepare the desired dosage of levofloxacin according to Table 5:
|Desired Dosage Strength||From Appropriate Vial,|
|Volume of Diluent||Infusion Time|
|250 mg||10 mL (20 mL Vial)||40 mL||60 min|
|500 mg||20 mL (20 mL Vial)||80 mL||60 min|
|750 mg||30 mL (30 mL Vial)||120 mL||90 min|
For example, to prepare a 500 mg dose using the 20 mL vial (25 mg/mL), withdraw 20 mL and dilute with a compatible intravenous solution to a total volume of 100 mL.
This intravenous drug product should be inspected visually for particulate matter prior to administration. Samples containing visible particles should be discarded.
Stability of LEVAQUIN® Injection Following Dilution: LEVAQUIN® Injection, when diluted in a compatible intravenous fluid to a concentration of 5 mg/mL, is stable for 72 hours when stored at or below 25°C (77°F) and for 14 days when stored under refrigeration at 5°C (41°F) in plastic intravenous containers. Solutions that are diluted in a compatible intravenous solution and frozen in glass bottles or plastic intravenous containers are stable for 6 months when stored at - 20°C (- 4°F). Thaw frozen solutions at room temperature 25°C (77°F) or in a refrigerator 8°C (46°F). Do not force thaw by microwave irradiation or water bath immersion. Do not refreeze after initial thawing.
LEVAQUIN® Injection Premix in Single-Use Flexible Containers (5 mg/mL)
LEVAQUIN® Injection is also supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use. The 100 mL premixed flexible containers contain either 250 mg/50 mL or 500 mg/100 mL of levofloxacin solution. The 150 mL flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL. No further dilution of these preparations is necessary. Because the premix flexible containers are for single-use only, any unused portion should be discarded.
Instructions for the Use of LEVAQUIN® Injection Premix in Flexible Containers:
Preparation for Administration:
TABLETS, Film-coated, capsule-shaped
ORAL SOLUTION, 25mg/mL, clear yellow to clear greenish-yellow color
INJECTION, Single-Use Vials of concentrated solution for dilution for intravenous infusion, clear yellow to clear greenish-yellow in appearance
INJECTION (5 mg/mL in 5% Dextrose) Premix in Single-Use Flexible Containers, for intravenous infusion
LEVAQUIN® is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.2)].
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including LEVAQUIN®. 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. LEVAQUIN® 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 (6); Patient Counseling Information (17.3)].
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including LEVAQUIN®. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
The drug should be discontinued immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions (6); Patient Counseling Information (17.3)].
Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with LEVAQUIN®. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 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 [see Warnings and Precautions (5.3)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6); Patient Counseling Information (17.3).]]
Convulsions and toxic psychoses have been reported in patients receiving fluoroquinolones, including LEVAQUIN®. 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. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN®, the drug should be discontinued and appropriate measures instituted. As with other fluoroquinolones, LEVAQUIN® 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.) [see Adverse Reactions (6); Drug Interactions (7.4, 7.5); Patient Counseling Information (17.3)].
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including LEVAQUIN®, 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.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
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 [see Adverse Reactions (6.2), Patient Counseling Information (17.3)].
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 LEVAQUIN®. LEVAQUIN® 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 [see Adverse Reactions (6), Patient Counseling Information (17.3)]
Some fluoroquinolones, including LEVAQUIN®, 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 fluoroquinolones, including LEVAQUIN®. LEVAQUIN® 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 [see Adverse Reactions (6.3), Use in Specific Populations (8.5), and Patient Counseling Information (17.3)].
LEVAQUIN® is indicated in pediatric patients (≥6 months of age) only for the prevention of inhalational anthrax (post-exposure) [see Indications and Usage (1.13)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving LEVAQUIN®[see Use in Specific Populations (8.4)].
In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].
As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with LEVAQUIN®, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with LEVAQUIN®, LEVAQUIN® should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions (6.2); Drug Interactions (7.3); Patient Counseling Information (17.4)].
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 fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].
Prescribing LEVAQUIN® 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 [see Patient Counseling Information (17.1)].
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
Hypotension has been associated with rapid or bolus intravenous infusion of LEVAQUIN®. LEVAQUIN® should be infused slowly over 60 to 90 minutes, depending on dosage [see Dosage and Administration (2.5)].
Crystalluria and cylindruria have been reported with quinolones, including LEVAQUIN®. Therefore, adequate hydration of patients receiving LEVAQUIN® should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5)].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to LEVAQUIN® in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with LEVAQUIN® for a wide variety of infectious diseases [see Indications and Usage (1)]. Patients received LEVAQUIN® doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3–14 days, and the mean number of days on therapy was 10 days.
The overall incidence, type and distribution of adverse reactions was similar in patients receiving LEVAQUIN® doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of LEVAQUIN® due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).
Adverse reactions occurring in ≥1% of LEVAQUIN®-treated patients and less common adverse reactions, occurring in 0.1 to <1% of LEVAQUIN®-treated patients, are shown in Table 6 and Table 7, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.
|System/Organ Class||Adverse Reaction||%
|Infections and Infestations||moniliasis||1|
|Psychiatric Disorders||insomnia* [see Warnings and Precautions (5.5)]
|Nervous System Disorders||headache|
dizziness [see Warnings and Precautions (5.5)]
|Respiratory, Thoracic and Mediastinal Disorders||dyspnea [see Warnings and Precautions (5.2)]||1|
|Skin and Subcutaneous Tissue Disorders||rash [see Warnings and Precautions (5.2)]
|Reproductive System and Breast Disorders||vaginitis||1†|
|General Disorders and Administration Site Conditions||edema||1|
|injection site reaction||1|
|System/Organ Class||Adverse Reaction|
|Infections and Infestations||genital moniliasis
|Blood and Lymphatic System Disorders||anemia
[see Warnings and Precautions (5.3)]
|Immune System Disorders
||allergic reaction [See Warnings and Precautions (5.2,5.3)]|
|Metabolism and Nutrition Disorders||hyperglycemia
[see Warnings and Precautions (5.10)]
[see Warnings and Precautions (5.5)]
|Nervous System Disorders||tremor
[see Warnings and Precautions (5.5)]
paresthesia [see Warnings and Precautions (5.7)]
|Respiratory, Thoracic and Mediastinal Disorders||epistaxis|
|Cardiac Disorders||cardiac arrest
pseudomembraneous/ C. difficile colitis [see Warnings and Precautions (5.6)]
|Hepatobiliary Disorders||abnormal hepatic function
increased hepatic enzymes
increased alkaline phosphatase
|Skin and Subcutaneous Tissue Disorders||urticaria [see Warnings and Precautions (5.2)]|
|Musculoskeletal and Connective Tissue Disorders||arthralgia
[see Warnings and Precautions (5.1)]
|Renal and Urinary Disorders||abnormal renal function
acute renal failure [see Warnings and Precautions (5.3)]
In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including LEVAQUIN®. The relationship of the drugs to these events is not presently established.
Table 8 lists adverse reactions that have been identified during post-approval use of LEVAQUIN®. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
|System/Organ Class||Adverse Reaction|
|Blood and Lymphatic System Disorders||pancytopenia
[see Warnings and Precautions (5.3)]
|Immune System Disorders||hypersensitivity reactions, sometimes fatal including:
[see Warnings and Precautions (5.2,5.3)]
isolated reports of suicide attempt and suicidal ideation
[see Warnings and Precautions (5.5)]
|Nervous System Disorders
peripheral neuropathy [see Warnings and Precautions (5.7)]
isolated reports of encephalopathy
abnormal electroencephalogram (EEG)
|Eye Disorders||vision disturbance, including diplopia
visual acuity reduced
|Ear and Labyrinth Disorders||hypoacusis
|Cardiac Disorders||isolated reports of torsade de pointes
electrocardiogram QT prolonged
[see Warnings and Precautions (5.8) ]
|Respiratory, Thoracic and Mediastinal Disorders||isolated reports of allergic pneumonitis [see Warnings and Precautions (5.3)]
|Hepatobiliary Disorders||hepatic failure (including fatal cases)
[see Warnings and Precautions (5.3),(5.4)]
|Skin and Subcutaneous Tissue Disorders||bullous eruptions to include:
toxic epidermal necrolysis
[see Warnings and Precautions (5.3)]
photosensitivity/phototoxicity reaction [see Warnings and Precautions (5.11)]
|Musculoskeletal and Connective Tissue Disorders||tendon rupture [see Warnings and Precautions (5.1)]
muscle injury, including rupture
|Renal and Urinary Disorders||interstitial nephritis [see Warnings and Precautions (5.3)].|
|General Disorders and Administration Site Conditions||multi-organ failure
|Investigations||prothrombin time prolonged
international normalized ratio prolonged
muscle enzymes increased
LEVAQUIN® Tablets and Oral Solution
While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of LEVAQUIN® Tablets and Oral Solution 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. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral LEVAQUIN® administration.
There are no data concerning an interaction of intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, no fluoroquinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.5)].
No significant effect of LEVAQUIN® on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that LEVAQUIN® enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and LEVAQUIN® use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if LEVAQUIN® is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3); Patient Counseling Information (17.4)].
Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions (5.10); Adverse Reactions (6.2), Patient Counseling Information (17.4)].
The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including LEVAQUIN®, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions (5.5)].
No significant effect of LEVAQUIN® on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, 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. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when LEVAQUIN® is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions (5.5)].
No significant effect of LEVAQUIN® on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin Cmax and ke were slightly lower while Tmax and t½ were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for LEVAQUIN® or cyclosporine when administered concomitantly.
No significant effect of LEVAQUIN® 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 LEVAQUIN® or digoxin is required when administered concomitantly.
No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t½ of levofloxacin were higher while CL/F and CLR were lower during concomitant treatment of LEVAQUIN® with probenecid or cimetidine compared to LEVAQUIN® alone. However, these changes do not warrant dosage adjustment for LEVAQUIN® when probenecid or cimetidine is co-administered.
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. LEVAQUIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Based on data on other fluoroquinolones and very limited data on LEVAQUIN®, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from LEVAQUIN® 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.
Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions (5.9) and Animal Toxicology and/or Pharmacology (13.2)].
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. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Indications and Usage (1.13), Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.9)].
In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous LEVAQUIN®. Children 6 months to 5 years of age received LEVAQUIN® 10 mg/kg twice a day and children greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days.
A subset of children in the clinical trials (1340 LEVAQUIN®-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendonopathy, gait abnormality) during 60 days and 1 year following the first dose of study drug. Children treated with LEVAQUIN® had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 9.
N = 1340
N = 893
|60 days||28 (2.1%)||8 (0.9%)||p = 0.038|
|1 year‡||46 (3.4%)||16 (1.8%)||p = 0.025|
Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) LEVAQUIN®-treated children and most were treated with analgesics. The median time to resolution was 7 days for LEVAQUIN®-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.
Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the LEVAQUIN®-treated and non-fluoroquinolone-treated children.
In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience [see Adverse Reactions (6)] may also be expected to occur in pediatric patients.
In phase 3 clinical trials, 1,945 LEVAQUIN®-treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN®. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.4)].
Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using LEVAQUIN® with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.8)].
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, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].
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 LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration (2.3)].
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.
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.
LEVAQUIN® is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.
Figure 1: The Chemical Structure of Levofloxacin
The empirical formula is C18H20FN3O4 • ½ 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 zwitterion at the pH conditions in the small intestine.
The data demonstrate that 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.
Excipients and Description of Dosage Forms
LEVAQUIN® Tablets are available as film-coated tablets and contain the following inactive ingredients:
LEVAQUIN® Oral Solution
LEVAQUIN® Oral Solution, 25 mg/mL, is a multi-use self-preserving aqueous solution of levofloxacin with pH ranging from 5.0 – 6.0. The appearance of LEVAQUIN® Oral Solution may range from clear yellow to clear greenish-yellow. This does not adversely affect product potency.
LEVAQUIN® Oral Solution contains the following inactive ingredients: sucrose, glycerin, sucralose, hydrochloric acid, purified water, propylene glycol, artificial and natural flavors, benzyl alcohol, ascorbic acid, and caramel color. It may also contain a solution of sodium hydroxide for pH adjustment.
The appearance of LEVAQUIN® Injection may range from a clear yellow to a clear greenish-yellow solution. This does not adversely affect product potency.
LEVAQUIN® Injection in Single-Use Vials is a sterile, preservative-free aqueous solution of levofloxacin in Water for Injection, with pH ranging from 3.8 to 5.8.
LEVAQUIN® Injection Premix in Single-Use Flexible Containers is a sterile, preservative-free aqueous solution of levofloxacin with pH ranging from 3.8 to 5.8. This is a dilute, non-pyrogenic, nearly isotonic premixed solution that contains levofloxacin in 5% Dextrose (D5W). Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH.
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.
Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Clinical Pharmacology (12.4)].
The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of LEVAQUIN® are summarized in Table 10.
2 volume of distribution/bioavailability
3 healthy males 18–53 years of age
4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose
5 healthy male and female subjects 18–54 years of age
6 500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin
7 dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling
8 healthy males 22–75 years of age
9 healthy females 18–80 years of age
10 young healthy male and female subjects 18–36 years of age
11 healthy elderly male and female subjects 66–80 years of age
12 healthy males and females 19–55 years of age.
*Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg tablet and F=0.99 ± 0.06 from a 750 mg tablet;
|250 mg oral tablet3||2.8 ± 0.4||1.6 ± 1.0||27.2 ± 3.9||156 ± 20||ND||7.3 ± 0.9||142 ± 21|
|500 mg oral tablet3*||5.1 ± 0.8||1.3 ± 0.6||47.9 ± 6.8||178 ± 28||ND||6.3 ± 0.6||103 ± 30|
|500 mg oral solution12||5.8 ± 1.8||0.8 ± 0.7||47.8 ± 10.8||183 ± 40||112 ± 37.2||7.0 ± 1.4||ND|
|500 mg IV3||6.2 ± 1.0||1.0 ± 0.1||48.3 ± 5.4||175 ± 20||90 ± 11||6.4 ± 0.7||112 ± 25|
|750 mg oral tablet5*||9.3 ± 1.6||1.6 ± 0.8||101 ± 20||129 ± 24||83 ± 17||7.5 ± 0.9||ND|
|750 mg IV5||11.5 ±4.04||ND||110 ±40||126 ±39||75 ± 13||7.5 ± 1.6||ND|
|500 mg every 24h oral tablet3||5.7 ± 1.4||1.1 ± 0.4||47.5 ± 6.7||175 ± 25||102 ± 22||7.6 ± 1.6||116 ± 31|
|500 mg every 24h IV3||6.4 ± 0.8||ND||54.6 ± 11.1||158 ± 29||91 ± 12||7.0 ± 0.8||99 ± 28|
|500 mg or 250 mg every 24h IV, patients with bacterial infection6||8.7± 4.07||ND||72.5 ± 51.27||154 ± 72||111 ± 58||ND||ND|
|750 mg every 24h oral tablet5||8.6 ± 1.9||1.4 ± 0.5||90.7 ± 17.6||143 ± 29||100 ± 16||8.8 ± 1.5||116 ± 28|
|750 mg every 24h IV5||12.1 ± 4.14||ND||108 ± 34||126 ± 37||80 ± 27||7.9 ± 1.9||ND|
|500 mg oral tablet single dose, effects of gender and age:|
|Male8||5.5 ± 1.1||1.2 ± 0.4||54.4 ± 18.9||166 ± 44||89 ± 13||7.5 ± 2.1||126 ± 38|
|Female9||7.0 ± 1.6||1.7 ± 0.5||67.7 ± 24.2||136 ± 44||62 ± 16||6.1 ± 0.8||106 ± 40|
|Young10||5.5 ± 1.0||1.5 ± 0.6||47.5 ± 9.8||182 ± 35||83 ± 18||6.0 ± 0.9||140 ± 33|
|Elderly11||7.0 ± 1.6||1.4 ± 0.5||74.7 ± 23.3||121 ± 33||67 ± 19||7.6 ± 2.0||91 ± 29|
|500 mg oral single dose tablet, patients with renal insufficiency:|
|CLCR 50–80 mL/min||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||7.1 ± 3.1||2.1 ± 1.3||182.1 ± 62.6||51 ± 19||ND||27 ± 10||26 ± 13|
|CLCR <20 mL/min||8.2 ± 2.6||1.1 ± 1.0||263.5 ± 72.5||33 ± 8||ND||35 ± 5||13 ± 3|
|Hemodialysis||5.7 ± 1.0||2.8 ± 2.2||ND||ND||ND||76 ± 42||ND|
|CAPD||6.9 ± 2.3||1.4 ± 1.1||ND||ND||ND||51 ± 24||ND|
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 LEVAQUIN® are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of LEVAQUIN® to healthy volunteers, the mean ±SD peak plasma concentration attained was 6.2 ±1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ±4.0 mcg/mL after a 750 mg dose infused over 90 minutes. LEVAQUIN® Oral Solution and Tablet formulations are bioequivalent.
Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ±1.4 and 0.5 ±0.2 mcg/mL after the 500 mg doses, and 8.6 ±1.9 and 1.1 ±0.4 mcg/mL after the 750 mg doses, respectively. 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 mcg/mL after the 500 mg doses, and 12.1 ±4.1 and 1.3 ±0.71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of LEVAQUIN® with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, LEVAQUIN® Tablets can be administered without regard to food. It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before, or 2 hours after eating.
The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for LEVAQUIN® Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure 2 and Figure 3).
|Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg|
|Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg|
The 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 and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of LEVAQUIN®, respectively, to healthy subjects. 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.
In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
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.
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 or intravenously. 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. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving LEVAQUIN®.
There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy elderly subjects (66 – 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. LEVAQUIN® dose adjustment based on age alone is not necessary [See Use in Specific Populations (8.5)].
The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent pharmacokinetic analyses predicted that a 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.
There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.
The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.
Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult 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 LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].
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 [See Use in Specific Populations (8.7)].
The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.
The potential for pharmacokinetic drug interactions between LEVAQUIN® and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions (7)].
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 mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.
Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.
Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-10). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Activity in vitro and in vivo
Levofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms.
Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications and Usage (1):
Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels as a surrogate marker in a rhesus monkey model for anthrax (post-exposure) [see Indications and Usage (1.13), Clinical Studies (14.9)].
The following in vitro data are available, but their clinical significance is unknown: Levofloxacin exhibits in vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of LEVAQUIN® in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Susceptibility testing for levofloxacin should be performed, as it is the optimal predictor of activity.
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC values). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of levofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 11.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg levofloxacin to test the susceptibility of microorganisms to levofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg levofloxacin disk should be interpreted according the criteria outlined in Table 11. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for levofloxacin.
(zone diameter in mm)
|S = Susceptible, I = Intermediate, R = Resistant|
|Streptococcus pneumonia||≤2§||4§||≥8§||≥17¶||14–16¶||≤13 ¶|
A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard levofloxacin powder should give the MIC values provided in Table 12. For diffusion technique, the 5 mcg levofloxacin disk should provide zone diameters provided in Table 12.
|MIC (mcg/mL)||Disk Diffusion
(zone diameter in mm)
|Enterococcus faecalis||ATCC 29212||0.25 – 2||Not applicable|
|Escherichia coli||ATCC 25922||0.008 – 0.06||29 – 37|
|Escherichia coli||ATCC 35218||0.015 – 0.06||Not applicable|
|Haemophilus influenzae||ATCC 49247||0.008 – 0.03*||32 – 40†|
|Pseudomonas aeruginosa||ATCC 27853||0.5 – 4||19 – 26|
|Staphylococcus aureus||ATCC 29213||0.06 – 0.5||Not applicable|
|Staphylococcus aureus||ATCC 25923||Not applicable||25 – 30|
|Streptococcus pneumoniae||ATCC 49619||0.5 – 2‡||20 – 25§|
In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the highest recommended human dose (750 mg) based upon relative body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of LEVAQUIN® averaged approximately 11.8 mcg/g at Cmax.
Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.
Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest recommended human dose based upon relative body surface area.
Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.9)]. In immature dogs (4–5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.
When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.
While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.
In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.
In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.
In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous LEVAQUIN® (750 mg once daily) followed by oral LEVAQUIN® (750 mg once daily) for a total of 7–15 days to intravenous imipenem/cilastatin (500–1000 mg every 6–8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7–15 days. LEVAQUIN®-treated patients received an average of 7 days of intravenous therapy (range: 1–16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1–19 days).
Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the LEVAQUIN® arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the LEVAQUIN® arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the LEVAQUIN® arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the LEVAQUIN® arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.
Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3–15 after completing therapy) were 58.1% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-17.2, 12.0]. The microbiological eradication rates at the posttherapy visit were 66.7% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of eradication rates (LEVAQUIN® minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 13.
|Pathogen||N||LEVAQUIN® No. (%) of |
Patients Microbiologic/Clinical Outcomes
|N||Imipenem/Cilastatin No. (%)
of Patients Microbiologic/Clinical Outcomes
|MSSA*||21||14 (66.7)/13 (61.9)||19||13 (68.4)/15 (78.9)|
|P. aeruginosa†||17||10 (58.8)/11 (64.7)||17||5 (29.4)/7 (41.2)|
|S. marcescens||11||9 (81.8)/7 (63.6)||7||2 (28.6)/3 (42.9)|
|E. coli||12||10 (83.3)/7 (58.3)||11||7 (63.6 )/8 (72.7)|
|K. pneumoniae‡||11||9 (81.8)/5 (45.5)||7||6 (85.7)/3 (42.9)|
|H. influenzae||16||13 (81.3)/10 (62.5)||15||14 (93.3)/11 (73.3)|
|S. pneumoniae||4||3 (75.0)/3 (75.0)||7||5 (71.4)/4 (57.1)|
Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing LEVAQUIN® 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with LEVAQUIN® at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg LEVAQUIN® administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 14.
|Pathogen||No. Pathogens||Microbiologic Eradication Rate (%)|
Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae
LEVAQUIN® was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/ml), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95.0%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 15.
|Screening Susceptibility||Clinical Success||Bacteriological Success*|
|2nd generation Cephalosporin resistant||31/32||96.9||31/32||96.9|
|Trimethoprim/ Sulfamethoxazole resistant||17/19||89.5||17/19||89.5|
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 16.
|Type of Resistance||Clinical Success||Bacteriologic Eradication|
|Resistant to 2 antibacterials||17/18 (94.4%)||17/18 (94.4%)|
|Resistant to 3 antibacterials||14/15 (93.3%)||14/15 (93.3%)|
|Resistant to 4 antibacterials||7/7 (100%)||7/7 (100%)|
|Resistant to 5 antibacterials||0||0|
|Bacteremia with MDRSP||8/9 (89%)||8/9 (89%)|
To evaluate the safety and efficacy of higher dose and shorter course of LEVAQUIN®, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg, IV or orally, every day for five days or LEVAQUIN® 500 mg IV or orally, every day for 10 days.
Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the LEVAQUIN® 750 mg group and 91.1% in the LEVAQUIN® 500 mg group. The 95% CI for the difference of response rates (LEVAQUIN® 750 minus LEVAQUIN® 500) was [-5.9, 5.4]. In the clinically evaluable population (31–38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the LEVAQUIN® 750 mg group and 2 out of 147 patients in the LEVAQUIN® 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 17.
|Penicillin susceptible S. pneumonia||19/20|
LEVAQUIN® is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth × 5 days or 500 mg by mouth once daily × 10–14 days. To evaluate the safety and efficacy of a high dose short course of LEVAQUIN®, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg by mouth once daily for five days to LEVAQUIN® 500 mg by mouth once daily for 10 days.
Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91.4% (139/152) in the LEVAQUIN® 750 mg group and 88.6% (132/149) in the LEVAQUIN® 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10.0] for LEVAQUIN® 750 mg minus LEVAQUIN® 500 mg).
Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day regimens at the test-of-cure visit 22 days post treatment.
|Pathogen||LEVAQUIN® 750 mg × 5 days||LEVAQUIN® 500 mg × 10 days|
|Streptococcus pneumoniae*||25/27 (92.6%)||26/27 (96.3%)|
|Haemophilus influenzae*||19/21 (90.5%)||25/27 (92.6%)|
|Moraxella catarrhalis*||10/11 (90.9%)||13/13 (100%)|
Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either LEVAQUIN® 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 ± 4.7 days. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the LEVAQUIN® and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the LEVAQUIN®-treated patients and 44% of the comparator treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication.
Among those who could be evaluated clinically 2–5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with LEVAQUIN® and 106/132 (80.3%) for patients treated with the comparator.
Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.
Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB3) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral LEVAQUIN® 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the LEVAQUIN® and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5–18 days after completion of therapy was 75.0% in the LEVAQUIN® group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for LEVAQUIN® minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 19.
|LEVAQUIN® (N=136)||Ciprofloxacin (N=125)|
|E. coli||15||14 (93.3%)||11||9 (81.8%)|
|E. faecalis||54||39 (72.2%)||44||33 (75.0%)|
|S. epidermidis*||11||9 (81.8%)||14||11 (78.6%)|
Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates.
Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5–18 days after completion of therapy were 75.0% for LEVAQUIN®-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for LEVAQUIN® minus ciprofloxacin). Clinical long-term success (24–45 days after completion of therapy) rates were 66.7% for the LEVAQUIN®-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for LEVAQUIN® minus ciprofloxacin).
To evaluate the safety and efficacy of the higher dose and shorter course of LEVAQUIN®, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing LEVAQUIN® 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of LEVAQUIN® and 5 to 9 days after the last dose of active ciprofloxacin.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.
|LEVAQUIN® 750 mg orally or IV once daily for 5 days||Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days||Overall Difference
|Overall (cUTI or AP)||252/333||75.7||239/318||75.2||0.5 (-6.1, 7.1)|
|Microbiologically Evaluable Population†|
|Overall (cUTI or AP)||228/265||86.0||215/241||89.2||-3.2 [-8.9, 2.5]|
Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to LEVAQUIN® treatment are presented in Table 21.
|Pathogen||Microbiologic Eradication Rate|
To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of LEVAQUIN®, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing LEVAQUIN® 250 orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1–12 days post-therapy in patients with a pathogen identified at baseline.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 22.
250 mg once daily for 10 days
500 mg twice daily for 10 days
|Microbiologically Evaluable Population‡||164/177||92.7||159/171||93.0|
The effectiveness of LEVAQUIN® for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of LEVAQUIN® associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.13); Dosage and Administration (2.1), (2.2)].
Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC0–24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].
In adults, the safety of LEVAQUIN® for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk.
In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendonopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions (5.9), Use in Specific Populations (8.4)].
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD50 (~2.7 × 106) spores (range 17 – 118 LD50) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC0–24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36.0 mcg.h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral LEVAQUIN® beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher's Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.
LEVAQUIN® Tablets are supplied as 250, 500, and 750 mg capsule-shaped, coated tablets. LEVAQUIN® Tablets are packaged in bottles and in unit-dose blister strips in the following configurations:
LEVAQUIN® Tablets should be stored at 15° to 30°C (59° to 86°F) in well-closed containers.
LEVAQUIN® Tablets are manufactured for PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 by Janssen Ortho LLC, Gurabo, Puerto Rico 00778.
LEVAQUIN® Oral Solution is supplied in a 16 oz. multi-use bottle (NDC 50458-170-01). Each bottle contains 480 mL of the 25 mg/mL levofloxacin oral solution
LEVAQUIN® Oral Solution should be stored at 25°C (77°F); excursions permitted to 15° – 30°C (59° to 86°F) [refer to USP controlled room temperature].
LEVAQUIN® Oral Solution is manufactured for PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 by Janssen Pharmaceutica N.V, Beerse, Belgium.
LEVAQUIN® Injection is supplied in single-use vials. Each vial contains a concentrated solution with the equivalent of 500 mg of levofloxacin in 20 mL vials and 750 mg of levofloxacin in 30 mL vials.
LEVAQUIN® Injection in Single-Use Vials should be stored at controlled room temperature and protected from light.
LEVAQUIN® Injection in Single-Use Vials is manufactured for Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 by Janssen Pharmaceutica N.V., Beerse, Belgium.
LEVAQUIN® (levofloxacin in 5% dextrose) Injection is supplied as a single-use, premixed solution in flexible containers. Each bag contains a dilute solution with the equivalent of 250, 500, or 750 mg of levofloxacin, respectively, in 5% Dextrose (D5W).
LEVAQUIN® Injection Premix in Flexible Containers should be stored at or below 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat and protect from freezing and light. LEVAQUIN® Injection Premix in Flexible Containers is manufactured for Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 by Hospira, Inc., Lake Forest, IL 60045.
Antibacterial drugs including LEVAQUIN® should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When LEVAQUIN® is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by LEVAQUIN® or other antibacterial drugs in the future.
Patients should be informed that LEVAQUIN® Tablets may be taken with or without food. LEVAQUIN® Oral Solution should be taken 1 hour before or 2 hours after eating. The tablet and oral solution should be taken at the same time each day.
Patients should drink fluids liberally while taking LEVAQUIN® to avoid formation of a highly concentrated urine and crystal formation in the urine.
Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral LEVAQUIN® administration.
Patients should be informed of the following serious adverse reactions that have been associated with LEVAQUIN® or other fluoroquinolone use:
Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue LEVAQUIN® and consult a physician.
Patients should be informed that concurrent administration of warfarin and LEVAQUIN® has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin concomitantly.
©Ortho-McNeil-Janssen Pharmaceuticals, Inc
U.S. Patent No. 5,053,407.
Issued July 2009
If you take too much, call your healthcare provider or get medical help immediately.
Store LEVAQUIN® Oral Solution at 59° to 86° F (15°C to 30°C).
levofloxacin tablet, film coated
|Labeler - Lake Erie Medical DBA Quality Care Products LLC (831276758)|
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