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 previously mentioned 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.
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 and toxic psychoses have been reported in patients receiving fluoroquinolones, including Levofloxacin. 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 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: 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 Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition.
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.
Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example: congenital long QT syndrome; concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics); uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia); elderly; cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse events including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis.
Vision Disorders: If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals: An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, 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 quinolones 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.
Use in the Elderly: In phase 3 clinical trials, 1,190 levofloxacin-treated patients (25%) were ≥ 65 years of age. Of these, 675 patients (14%) were between the ages of 65 and 74 and 515 patients (11%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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 patents 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.