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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 27.03.2022
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Dosage Forms And Strengths
ORAL SOLUTION, 25 mg/mL, clear yellow to clear greenish-yellow color
Storage And Handling
Levofloxacin Oral Solution
Levofloxacin Oral Solution is supplied in a 16 oz. multi-use bottle (NDC 10147-0941-6). Each bottle contains 480 mL of the 25 mg/mL levofloxacin oral solution.
Levofloxacin 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].
Levofloxacin Oral Solution is manufactured for Patriot Pharmaceuticals, LLC, Horsham, PA 19044 by Janssen Pharmaceutica N.V., Beerse, Belgium.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Levofloxacin and other antibacterial drugs, Levofloxacin 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.
Levofloxacin Oral Solution are indicated for the treatment of adults ( ≥ 18 years of age) with mild, moderate, and severe infections caused by susceptible isolates of the designated microorganisms in the conditions listed in this section.
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. Therapy with Levofloxacin 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 isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with Levofloxacin. 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.
Nosocomial Pneumonia
Levofloxacin 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.
Community-Acquired Pneumonia: 7-14 Day Treatment Regimen
Levofloxacin is indicated for the treatment of community-acquired pneumonia due to methicillinsusceptible 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.
MDRSP isolates are isolates 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.
Community-Acquired Pneumonia: 5-Day Treatment Regimen
Levofloxacin is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae.
Acute Bacterial Sinusitis : 5-Day And 10-14 Day Treatment Regimens
Levofloxacin is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.
Acute Bacterial Exacerbation Of Chronic Bronchitis
Levofloxacin 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.
Complicated Skin And Skin Structure Infections
Levofloxacin 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 .
Uncomplicated Skin And Skin Structure Infections
Levofloxacin 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.
Chronic Bacterial Prostatitis
Levofloxacin is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis.
Complicated Urinary Tract Infections : 5-Day Treatment Regimen
Levofloxacin is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis.
Complicated Urinary Tract Infections : 10-Day Treatment Regimen
Levofloxacin 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.
Acute Pyelonephritis : 5 Or 10-Day Treatment Regimen
Levofloxacin is indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia.
Uncomplicated Urinary Tract Infections
Levofloxacin is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.
Inhalational Anthrax (Post-Exposure)
Levofloxacin is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of Levofloxacin is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of Levofloxacin 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 Levofloxacin therapy should only be used when the benefit outweighs the risk.
Plague
Levofloxacin is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients, 6 months of age and older. Efficacy studies of Levofloxacin could not be conducted in humans with plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals .
Dosage In Adult Patients With Normal Renal Function
The usual dose of Levofloxacin Oral Solution is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1.
These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance < 50 mL/min, adjustments to the dosing regimen are required.
Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min)
| 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 |
| 500 mg | 10-14 | |
| 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)¶ | 750 mg | 5 |
| 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 Pediatric patients < 50 kg and ≥ 6 months of ageÞ,β | 500 mg | 60β |
| see Table 2 below (2.2) | 60β | |
| Plague, adult and pediatric patients > 50 kgà a Pediatric patients < 50 kg and ≥ 6 months of age | 500 mg | 10 to 14 |
| see Table 2 below (2.2) | 10 to 14 | |
| *Due to the designated pathogens. †Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae. §Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae. ¶This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. #This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli. ÞDrug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit. βThe safety of Levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients. Prolonged Levofloxacin therapy should only be used when the benefit outweighs the risk. àDrug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of Levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated. |
Dosage In Pediatric Patients
The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.
Table 2: Dosage in Pediatric Patients ≥ 6 months
of age
| Type of Infection* | Dose | Freq. Once every | Duration† |
| Inhalational Anthrax (post-exposure)‡,§ | |||
| Pediatric patients > 50 kg | 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§ |
| Plague¶ | |||
| Pediatric patients > 50 kg | 500 mg | 24 hr | 10 to 14 days |
| Pediatric patients < 50 kg and ≥ 6 months of age | 8 mg/kg (not to exceed 250 mg per dose) | 12 hr | 10 to 14 days |
| *Due to Bacillus anthracis and Yersinia pestis. †Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit §The safety of Levofloxacin in pediatric patients for durations of therapy beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients. Prolonged Levofloxacin therapy should only be used when the benefit outweighs the risk. ¶Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. |
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Dosage Adjustment In Adults With Renal Impairment
Administer Levofloxacin 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.
Table 3 shows how to adjust dose based on creatinine clearance.
Table 3: Dosage Adjustment in Adult Patients with
Renal Impairment (creatinine clearance < 50 mL/min)
| Dosage in Normal Renal Function Every 24 hours | Creatinine Clearance 20 to 49 mL/min | Creatinine Clearance 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 |
Drug Interaction With Chelation Agents : Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin Oral Solution
Levofloxacin 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.
Administration Instructions
Food And Levofloxacin Oral Solution
It is recommended that Levofloxacin Oral Solution be taken 1 hour before or 2 hours after eating.
Hydration For Patients Receiving Levofloxacin Oral Solution
Adequate hydration of patients receiving oral Levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones.
Levofloxacin is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Tendinopathy And Tendon Rupture
Fluoroquinolones, including Levofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Levofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug..
Exacerbation Of Myasthenia Gravis
Fluoroquinolones, including Levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Levofloxacin in patients with a known history of myasthenia gravis.
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including Levofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. 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 .
Other Serious And Sometimes Fatal Reactions
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 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; 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 drug should be discontinued immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted.
Hepatotoxicity
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 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. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis.
Central Nervous System Effects
Convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including Levofloxacin. Fluoroquinolones may also cause 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 Levofloxacin, the drug should be discontinued and appropriate measures instituted. As with other fluoroquinolones, Levofloxacin should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction)..
Clostridium Difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Levofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
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.
Peripheral Neuropathy
Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including Levofloxacin. Symptoms may occur soon after initiation of Levofloxacin and may be irreversible. Levofloxacin should be discontinued immediately 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.
Prolongation Of The QT Interval
Some fluoroquinolones, including Levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including Levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Musculoskeletal Disorders In Pediatric Patients And Arthropathic Effects In Animals
Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levofloxacin.
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.
Blood Glucose Disturbances
As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with Levofloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with Levofloxacin, Levofloxacin should be discontinued and appropriate therapy should be initiated immediately.
Photosensitivity/Phototoxicity
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.
Development Of Drug Resistant Bacteria
Prescribing Levofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Patient Counseling Information
See FDA-Approved Medication Guide
Antibacterial Resistance
Antibacterial drugs including Levofloxacin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Levofloxacin 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 Levofloxacin or other antibacterial drugs in the future.
Administration with Food, Fluids, And Concomitant Medications
Levofloxacin Oral Solution should be taken 1 hour before or 2 hours after eating. The oral solution should be taken at the same time each day.
Patients should drink fluids liberally while taking Levofloxacin 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 Levofloxacin administration.
Serious And Potentially Serious Adverse Reactions
Patients should be informed of the following serious adverse reactions that have been associated with Levofloxacin or other fluoroquinolone use:
- Tendon Disorders : Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue Levofloxacin treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung trans plants.
- Exacerbation of Myasthenia Gravis : Patients should inform their physician of any history of myasthenia gravis. Patients should notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
- Hypersensitivity Reactions : Patients should be informed that Levofloxacin can cause hypersensitivity reactions, even following the first dose. Patients should discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
- Hepatotoxicity: Severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking Levofloxacin. Patients should inform their physician and be instructed to discontinue Levofloxacin treatment immediately if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
- Convulsions : Convulsions have been reported in patients taking fluoroquinolones, including Levofloxacin. Patients should notify their physician before taking this drug if they have a history of convulsions.
- Neurologic Adverse Effects (e.g., dizziness, lightheadedness, increased intracranial pressure): Patients should know how they react to Levofloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Patients should notify their physician if persistent headache with or without blurred vision occurs.
- Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
- Peripheral Neuropathies : Patients should be informed that peripheral neuropathy has been associated with Levofloxacin use. Symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue treatment and contact their physician.
- Prolongation of the QT Interval: Patients should inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Patients should notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
- Musculoskeletal Disorders in Pediatric Patients : Parents should inform their child's physician if their child has a history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their child's physician of any tendon or joint-related problems that occur during or following Levofloxacin therapy.
- Photosensitivity/Phototoxicity: Patients should be advised that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolone antibiotics. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors when taking fluoroquinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn like reaction or skin eruption occurs, patients should contact their physician.
Drug Interactions With Insulin, Oral Hypoglycemic Agents, And Warfarin
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 Levofloxacin and consult a physician.
Patients should be informed that concurrent administration of warfarin and Levofloxacin 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.
Plague And Anthrax Studies
Patients given Levofloxacin for these conditions should be informed that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 Levofloxacin 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.
Use In Specific Populations
Pregnancy
Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area.
There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Based on data on other fluoroquinolones and very limited data on Levofloxacin, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from Levofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species..
Inhalational Anthrax (Post-Exposure)
Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (postexposure). 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.
Plague
Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of Levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate.
Safety and effectiveness in pediatric patients below the age of six months have not been established.
Adverse Events
In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous Levofloxacin. Children 6 months to 5 years of age received Levofloxacin 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 Levofloxacin-treated and 893 non-fluoroquinolonetreated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocoldefined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Children treated with Levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the nonfluoroquinolone- treated children as illustrated in Table 7.
Table 7: Incidence of Musculoskeletal Disorders in Pediatric
Clinical Trial
| Follow-up Period | Levofloxacin N =1340 |
Non-Fluoroquinolone* N = 893 |
p-value† |
| 60 days | 28 (2.1%) | 8 (0.9%) | p = 0.038 |
| 1 year‡ | 46 (3.4%) | 16 (1.8%) | p = 0.025 |
| *Non-Fluoroquinolone: ceftriaxone,
amoxicillin/clavulanate, clarithromycin †2-sided Fisher's Exact Test ‡There were 1199 Levofloxacin-treated and 804 non-fluoroquinolone-treated children who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all children enrolled regardless of whether they completed the 1- year evaluation visit. |
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%) Levofloxacin-treated children and most were treated with analgesics. The median time to resolution was 7 days for Levofloxacin-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 Levofloxacin-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 may also be expected to occur in pediatric patients.
Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
In Phase 3 clinical trials, 1,945 Levofloxacin-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 Levofloxacin. 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.
Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Levofloxacin 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).
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.
Renal Impairment
Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of Levofloxacin are not required following hemodialysis or CAPD.
Hepatic Impairment
Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.
SIDE EFFECTS
Serious And Otherwise Important Adverse Reactions
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Tendon Effects
- Exacerbation of Myasthenia Gravis
- Hypersensitivity Reactions
- Other Serious and Sometimes Fatal Reactions
- Hepatotoxicity
- Central Nervous System Effects
- Clostridium difficile-Associated Diarrhea
- Peripheral Neuropathy that may be irreversible
- Prolongation of the QT Interval
- Musculoskeletal Disorders in Pediatric Patients
- Blood Glucose Disturbances
- Photosensitivity/Phototoxicity
- Development of Drug Resistant Bacteria
Crystalluria and cylindruria have been reported with quinolones, including Levofloxacin. Therefore, adequate hydration of patients receiving Levofloxacin should be maintained to prevent the formation of a highly concentrated urine.
Clinical Trial Experience
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 Levofloxacin 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 Levofloxacin for a wide variety of infectious diseases. Patients received Levofloxacin 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 Levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of Levofloxacin 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 Levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to < 1% of Levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions ( ≥ 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.
Table 4: Common ( ≥ 1%) Adverse Reactions Reported
in Clinical Trials with Levofloxacin
| System/Organ Class | Adverse Reaction | % (N=7537) |
| Infections and Infestations | moniliasis | 1 |
| Psychiatric Disorders | insomnia* | 4 |
| Nervous System Disorders | headache dizziness | 6 3 |
| Respiratory, Thoracic and Mediastinal Disorders | dyspnea | 1 |
| nausea | 7 | |
| diarrhea | 5 | |
| Gas tro inte s tinal Disorders | constipation | 3 |
| abdominal pain | 2 | |
| vomiting | 2 | |
| dyspepsia | 2 | |
| Skin and Subcutaneous Tissue Disorders | rash | 2 |
| pruritus | 1 | |
| Reproductive System and Breast Disorders | vaginitis | 1† |
| General Disorders and Administration Site Conditions | edema | 1 |
| injection site reaction | 1 | |
| chest pain | 1 | |
| *N=7274 †N=3758 (women) |
Table 5: Less Common (0.1 to 1%) Adverse Reactions
Reported in Clinical Trials with Levofloxacin (N=7537)
| System/Organ Class | Adverse Reaction |
| Infections and Infestations | genital moniliasis |
| Blood and Lymphatic System Disorders | anemia thrombocytopenia granulocytopenia |
| Immune System Disorders | allergic reaction |
| Metabolism and Nutrition Disorders | hyperglycemia hypoglycemia hyperkalemia |
| Psychiatric Disorders | anxiety agitation confusion depression hallucination nightmare* sleep disorder* anorexia abnormal dreaming* tremor convulsions |
| Nervous System Disorders | paresthesia vertigo hypertonia hyperkinesias abnormal gait somnolence* syncope |
| Respiratory, Thoracic and Mediastinal Disorders | epistaxis |
| Cardiac Disorders | cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia |
| Vascular Disorders | phlebitis |
| Gastrointestinal Disorders | gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C. difficile colitis |
| Hepatobiliary Disorders | abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase |
| Skin and Subcutaneous Tissue Disorders | urticaria |
| Musculoskeletal and Connective Tissue Disorders | arthralgia tendinitis myalgia skeletal pain |
| Renal and Urinary Disorders | abnormal renal function acute renal failure |
| *N = 7274 |
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 Levofloxacin. The relationship of the drugs to these events is not presently established.
Postmarketing Experience
Table 6 lists adverse reactions that have been identified during post-approval use of Levofloxacin. 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.
Table 6: Postmarketing Reports Of Adverse Drug
Reactions
| System/Organ Class | Adverse Reaction |
| Blood and Lymphatic System Disorders | pancytopenia aplastic anemia leukopenia hemolytic anemia eosinophilia |
| Immune System Disorders | hypersensitivity reactions, sometimes fatal including: anaphyl actic /anaphyl actoid reactions anaphylactic shock angioneurotic edema serum sickness |
| Psychiatric Disorders | psychosis paranoia isolated reports of suicide attempt and suicidal ideation |
| Nervous System Disorders | exacerbation of myasthenia gravis anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri |
| Eye Disorders | uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma |
| Ear and Labyrinth Disorders | hypoacusis tinnitus |
| Cardiac Disorders | isolated reports of torsade de pointes electrocardiogram QT prolonged tachycardia |
| Vascular Disorders | vasodilatation |
| Respiratory, Thoracic and Mediastinal Disorders | isolated reports of allergic pneumonitis |
| Hepatobiliary Disorders | hepatic failure (including fatal cases) hepatitis jaundice |
| Skin and Subcutaneous Tissue Disorders | bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme photosensitivity/phototoxicity reaction leukocytoclastic vasculitis |
| Musculoskeletal and Connective Tissue Disorders | tendon rupture muscle injury, including rupture rhabdomyolysis |
| Renal and Urinary Disorders | interstitial nephritis |
| General Disorders and Administration Site Conditions | multi-organ failure pyrexia |
| Investigations | prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased |
DRUG INTERACTIONS
Chelation Agents : Antacids, Sucralfate, Metal Cations, Multivitamins Levofloxacin Oral Solution
While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of Levofloxacin 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 multivitamin 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 Levofloxacin administration.
Warfarin
No significant effect of Levofloxacin 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 Levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and Levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if Levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.
Antidiabetic Agents
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.
Non-Steroidal Anti-Inflammatory Drugs
The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including Levofloxacin, may increase the risk of CNS stimulation and convulsive seizures.
Theophylline
No significant effect of Levofloxacin 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 Levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels.
Cyclosporine
No significant effect of Levofloxacin 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 coadministered 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 Levofloxacin or cyclosporine when administered concomitantly.
Digoxin
No significant effect of Levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for Levofloxacin or digoxin is required when administered concomitantly.
Probenecid And Cimetidine
No significant effect of probenecid or cimetidine on the C 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 Levofloxacin with probenecid or cimetidine compared to Levofloxacin alone. However, these changes do not warrant dosage adjustment for Levofloxacin when probenecid or cimetidine is co-administered.
Interactions With Laboratory Or Diagnostic Testing
Some fluoroquinolones, including Levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.
Pregnancy Category C. Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based upon relative body surface area. The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area.
There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Serious And Otherwise Important Adverse Reactions
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Tendon Effects
- Exacerbation of Myasthenia Gravis
- Hypersensitivity Reactions
- Other Serious and Sometimes Fatal Reactions
- Hepatotoxicity
- Central Nervous System Effects
- Clostridium difficile-Associated Diarrhea
- Peripheral Neuropathy that may be irreversible
- Prolongation of the QT Interval
- Musculoskeletal Disorders in Pediatric Patients
- Blood Glucose Disturbances
- Photosensitivity/Phototoxicity
- Development of Drug Resistant Bacteria
Crystalluria and cylindruria have been reported with quinolones, including Levofloxacin. Therefore, adequate hydration of patients receiving Levofloxacin should be maintained to prevent the formation of a highly concentrated urine.
Clinical Trial Experience
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 Levofloxacin 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 Levofloxacin for a wide variety of infectious diseases. Patients received Levofloxacin 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 Levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of Levofloxacin 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 Levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to < 1% of Levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions ( ≥ 3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.
Table 4: Common ( ≥ 1%) Adverse Reactions Reported
in Clinical Trials with Levofloxacin
| System/Organ Class | Adverse Reaction | % (N=7537) |
| Infections and Infestations | moniliasis | 1 |
| Psychiatric Disorders | insomnia* | 4 |
| Nervous System Disorders | headache dizziness | 6 3 |
| Respiratory, Thoracic and Mediastinal Disorders | dyspnea | 1 |
| nausea | 7 | |
| diarrhea | 5 | |
| Gas tro inte s tinal Disorders | constipation | 3 |
| abdominal pain | 2 | |
| vomiting | 2 | |
| dyspepsia | 2 | |
| Skin and Subcutaneous Tissue Disorders | rash | 2 |
| pruritus | 1 | |
| Reproductive System and Breast Disorders | vaginitis | 1† |
| General Disorders and Administration Site Conditions | edema | 1 |
| injection site reaction | 1 | |
| chest pain | 1 | |
| *N=7274 †N=3758 (women) |
Table 5: Less Common (0.1 to 1%) Adverse Reactions
Reported in Clinical Trials with Levofloxacin (N=7537)
| System/Organ Class | Adverse Reaction |
| Infections and Infestations | genital moniliasis |
| Blood and Lymphatic System Disorders | anemia thrombocytopenia granulocytopenia |
| Immune System Disorders | allergic reaction |
| Metabolism and Nutrition Disorders | hyperglycemia hypoglycemia hyperkalemia |
| Psychiatric Disorders | anxiety agitation confusion depression hallucination nightmare* sleep disorder* anorexia abnormal dreaming* tremor convulsions |
| Nervous System Disorders | paresthesia vertigo hypertonia hyperkinesias abnormal gait somnolence* syncope |
| Respiratory, Thoracic and Mediastinal Disorders | epistaxis |
| Cardiac Disorders | cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia |
| Vascular Disorders | phlebitis |
| Gastrointestinal Disorders | gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C. difficile colitis |
| Hepatobiliary Disorders | abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase |
| Skin and Subcutaneous Tissue Disorders | urticaria |
| Musculoskeletal and Connective Tissue Disorders | arthralgia tendinitis myalgia skeletal pain |
| Renal and Urinary Disorders | abnormal renal function acute renal failure |
| *N = 7274 |
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 Levofloxacin. The relationship of the drugs to these events is not presently established.
Postmarketing Experience
Table 6 lists adverse reactions that have been identified during post-approval use of Levofloxacin. 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.
Table 6: Postmarketing Reports Of Adverse Drug
Reactions
| System/Organ Class | Adverse Reaction |
| Blood and Lymphatic System Disorders | pancytopenia aplastic anemia leukopenia hemolytic anemia eosinophilia |
| Immune System Disorders | hypersensitivity reactions, sometimes fatal including: anaphyl actic /anaphyl actoid reactions anaphylactic shock angioneurotic edema serum sickness |
| Psychiatric Disorders | psychosis paranoia isolated reports of suicide attempt and suicidal ideation |
| Nervous System Disorders | exacerbation of myasthenia gravis anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri |
| Eye Disorders | uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma |
| Ear and Labyrinth Disorders | hypoacusis tinnitus |
| Cardiac Disorders | isolated reports of torsade de pointes electrocardiogram QT prolonged tachycardia |
| Vascular Disorders | vasodilatation |
| Respiratory, Thoracic and Mediastinal Disorders | isolated reports of allergic pneumonitis |
| Hepatobiliary Disorders | hepatic failure (including fatal cases) hepatitis jaundice |
| Skin and Subcutaneous Tissue Disorders | bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme photosensitivity/phototoxicity reaction leukocytoclastic vasculitis |
| Musculoskeletal and Connective Tissue Disorders | tendon rupture muscle injury, including rupture rhabdomyolysis |
| Renal and Urinary Disorders | interstitial nephritis |
| General Disorders and Administration Site Conditions | multi-organ failure pyrexia |
| Investigations | prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased |
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of Levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.
The mean ± SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of Levofloxacin are summarized in Table 8.
Table 8: Mean ± SD Levofloxacin PK Parameters
| Regimen | Cmax (mcg/mL) | Tmax (h) | AUC (mcg•h/mL) | CL/F* (mL/min) | Vd/F† (L) | t½(h) | CLr (mL/min) |
| Single dose | |||||||
| 250 mg oral tablet‡ | 2.8 ± 0.4 | 1.6 ± 1.0 | 27.2 ± 3.9 | 156 ± 20 | ND | 7.3 ± 0.9 | 142 ± 21 |
| 500 mg oral tablet‡§ | 5.1 ± 0.8 | 1.3 ± 0.6 | 47.9 ± 6.8 | 178 ± 28 | ND | 6.3 ± 0.6 | 103 ± 30 |
| 500 mg oral solution¶ | 5.8 ± 1.8 | 0.8 ± 0.7 | 47.8 ± 10.8 | 183 ± 40 | 112 ± 37.2 | 7.0 ± 1.4 | ND |
| 500 mg IV‡ | 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 tablet#§ | 9.3 ± 1.6 | 1.6 ± 0.8 | 101 ± 20 | 129 ± 24 | 83 ± 17 | 7.5 ± 0.9 | ND |
| 750 mg IV# | 11.5 ± 4.0Þ | ND | 110 ± 40 | 126 ± 39 | 75 ± 13 | 7.5 ± 1.6 | ND |
| Multiple dose | |||||||
| 500 mg every 24h oral tablet‡ | 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 IV‡ | 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 infectionβ | 8.7± 4.0à | ND | 72.5 ± 51.2à | 154 ± 72 | 111 ± 58 | ND | ND |
| 750 mg every 24h oral tablet# | 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 IV# | 12.1 ± 4.1Þ | ND | 108 ± 34 | 126 ± 37 | 80 ± 27 | 7.9 ± 1.9 | ND |
| 500 mg oral single dose tablet, patients with renal ins ufficiency: | |||||||
| Maleè | 5.5 ± 1.1 | 1.2 ± 0.4 | 54.4 ± 18.9 | 166 ± 44 | 89 ± 13 | 7.5 ± 2.1 | 126 ± 38 |
| Femaleð | 7.0 ± 1.6 | 1.7 ± 0.5 | 67.7 ± 24.2 | 136 ± 44 | 62 ± 16 | 6.1 ± 0.8 | 106 ± 40 |
| Youngø | 5.5 ± 1.0 | 1.5 ± 0.6 | 47.5 ± 9.8 | 182 ± 35 | 83 ± 18 | 6.0 ± 0.9 | 140 ± 33 |
| Elderlyý | 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 sin | gle 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 |
| ND=not determined. *clearance/bioavailability †volume of distribution/bioavailability ‡healthy males 18–53 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; ¶healthy males and females 19–55 years of age. #healthy male and female subjects 18–54 years of age Þ60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose β500 mg every 4 8h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin àdose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling èhealthy males 22–75 years of age ðhealthy females 18–80 years of age øyoung healthy male and female subjects 18–36 years of age ýhealthy elderly male and female subjects 66–80 years of age |
|||||||
Absorption
Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of Levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of Levofloxacin 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. Levofloxacin 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 oncedaily 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 Levofloxacin 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, Levofloxacin Tablets can be administered without regard to food. It is recommended that Levofloxacin 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 Levofloxacin 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
Distribution
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 Levofloxacin, 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.
Metabolism
Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion
Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally 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 Levofloxacin.
Geriatric
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 Levofloxacin 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. Levofloxacin dose adjustment based on age alone is not necessary.
Pediatrics
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.
Gender
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 Levofloxacin to healthy male subjects, the mean terminal plasma elimination halflife 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.
Race
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.
Renal Impairment
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 Levofloxacin are not required following hemodialysis or CAPD.
Hepatic Impairment
Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.
Bacterial Infection
The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.
