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Methicillin-resistant Staphylococcus aureus (MRSA): Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA infections are considered inappropriate).
Clostridium difficile-associated diarrhea (CDAD): This has been observed with the use of nearly all antibacterial agents, including levofloxacin, and may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea following administration of antibacterial agents.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases.
Tendinitis 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. This risk is further increased in those over 60 years old, in kidney, heart, or lung transplant recipients, and with concomitant steroid therapy. Strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis may also increase the risk of tendon rupture. 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 doctor about 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. Post-marketing reports of serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Levofloxacin should be avoided in patients with known history of myasthenia gravis.
Musculoskeletal Disorders in Children: Levofloxacin is indicated in children ≥6 months old 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.
Oral and IV administration of levofloxacin in immature rats and dogs increased the incidence and severity of 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.
Hepatotoxicity: Severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients treated with levofloxacin. Most cases of severe hepatotoxicity occurred within 6 to 14 days of initiation of levofloxacin therapy and were not associated with hypersensitivity reactions; the majority of fatal cases occurred in patients 65 years and older.
Levofloxacin should be discontinued in any patient who experiences loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin or eyes, light colored bowel movement, or dark colored urine.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolones, including levofloxacin. These reactions often occur after the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, larynx, 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, IV 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 treatment with fluoroquinolones, including levofloxacin. Clinical manifestations which may be severe and generally occur after multiple doses 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. Levofloxacin should be discontinued immediately at the first appearance of skin rash or any other sign of hypersensitivity and supportive measures instituted.
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/ phototoxicity reactions manifesting as exaggerated sunburn reaction have been observed in patients exposed to direct sunlight or ultraviolet (UV) light while receiving fluoroquinolones; hence, direct exposure to excessive sunlight or UV radiation should be avoided during treatment. Therapy should be discontinued if photosensitization occurs.
Central Nervous System (CNS) Disorders: Convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including levofloxacin. Fluoroquinolones may also cause CNS stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, anxiety, and rarely, suicidal thoughts or acts. These reactions may occur after the first dose. If these reactions occur in patients receiving levofloxacin, the drug should be discontinued and appropriate measures instituted. As with other quinolones, levofloxacin should be used with caution in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy), or other risk factors (e.g., certain drug therapy, renal impairment) that may predispose to seizures or lower the seizure threshold.
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.
Cardiac Disorders: Prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia have been reported with some fluoroquinolones, including levofloxacin. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, significant bradycardia, cardiomyopathy, or myocardial ischemia. The risk of arrhythmias may be reduced by avoiding concomitant use with other drugs that prolong the QT interval including macrolide antibiotics, antipsychotics, tricyclic antidepressants, class IA (quinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmic agents, and cisapride. Elderly patients generally may be more susceptible to drug-associated effects on the QT interval.
Renal: The risk of toxic reactions to levofloxacin may be greater in patients with impaired renal function since levofloxacin is known to be substantially excreted by the kidney. Adjustment of the dosage regimen may be necessary to avoid the accumulation of levofloxacin due to decreased clearance. Careful observation and appropriate laboratory studies should be done prior to and during therapy, since elimination of levofloxacin may be reduced. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Administer levofloxacin with caution in the presence of renal insufficiency.
Blood Glucose Disturbances: As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper-and hypoglycemia, have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. Careful monitoring of blood glucose is recommended in these patients. Levofloxacin should be discontinued and appropriate therapy initiated immediately if a hypoglycemic reaction occurs. Serious hypoglycemia and hyperglycemia have also occurred in patients without a history of diabetes. Hypoglycemic coma has been observed in diabetic patients on levofloxacin therapy. Fatal outcomes have been reported. All cases of hypoglycemic coma had multiple confounding factors; a temporal relationship with the use of levofloxacin was identified (onset of altered consciousness occurred within 3 days in most cases). Caution should be exercised when using levofloxacin in diabetic patients taking concomitant treatment with an oral hypoglycemic agent and/or insulin, particularly those who are elderly or who have renal impairment.
Patients with G-6-phosphate dehydrogenase deficiency: Use with caution in patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity who may be prone to hemolytic reactions when treated with fluoroquinolones.
Other Precautions: As with any potent antimicrobial drug, periodic assessment of organ including renal, hepatic, and hematopoietic, is advisable during treatment.
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.
Levofloxacin is not indicated for the treatment of syphilis or gonorrhea. Levofloxacin is not effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with antimicrobial agents with limited or no activity against Treponema pallidum should have a follow-up serologic test for syphilis after 3 months.
As with other antibacterial drugs, long term or repeated use may result in overgrowth of non-susceptible organisms, including fungi.
Effects on Ability to Drive and Use Machines: Since there is a potential for levofloxacin to cause dizziness and lightheadedness, patients should be advised to avoid performing tasks which require complete mental alertness such as driving and operating machinery until effects of drug to the individual are known.
Renal Impairment: Since clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (creatinine clearance <50 mL/min), adjustment of the dosage regimen in such patients is necessary to avoid drug accumulation.
Hepatic Impairment: Pharmacokinetic studies in patients with liver impairment 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.
Use in Children: Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. In a prospective long-term surveillance study, the incidence of protocol-defined musculoskeletal disorders was higher in children treated for approximately 10 days with levofloxacin than in children treated with non-fluoroquinolone antibiotics for approximately 10 days.
Use in the Elderly: There is no substantial difference in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.
Risk of severe tendon disorder, including tendon rupture, is increased in older adults, usually those older than 60 years old. This risk is further increased in those receiving concomitant corticosteroids. Caution is advised in geriatric adults, particularly those receiving concomitant corticosteroids.
Risk of fatal hepatotoxicity may be increased in geriatric patients. Risk of prolonged QT interval leading to ventricular arrhythmias may be increased in geriatric patients, particularly those receiving concurrent therapy with other drugs that can prolong QT interval (e.g., class IA or III antiarrhythmic agents) or with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
