WARNINGS AND PRECAUTIONS
5.1 Tendinopathy and Tendon Rupture
Fluoroquinolones, including LEVAQUIN®, 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. LEVAQUIN® 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. [ see Adverse Reactions (6.3); Patient Counseling Information (17.3) ].
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including LEVAQUIN®. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. LEVAQUIN® should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines,corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions Patient Counseling Information].
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 LEVAQUIN®. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
- 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 [see Adverse Reactions Patient Counseling Information].
Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with LEVAQUIN®. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [ see Warnings and Precautions ]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN ® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [ see Adverse Reactions Patient Counseling Information ].
Central Nervous System Effects
Convulsions and toxic psychoses have been reported in patients receiving fluoroquinolones, including LEVAQUIN®. Fluoroquinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN®, the drug should be discontinued and appropriate measures instituted. As with other fluoroquinolones, LEVAQUIN® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction.) [see Adverse Reactions (6) ; Drug Interactions (7.4, 7.5) ; Patient Counseling Information].
Clostridium difficile-Associated Diarrhea
Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including LEVAQUIN ®, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions, Patient Counseling Information].
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including LEVAQUIN®. LEVAQUIN® should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition [see Adverse Reactions (6), Patient Counseling Information].
Prolongation of the QT Interval
Some fluoroquinolones, including LEVAQUIN®, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including LEVAQUIN®. LEVAQUIN® should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions, Use in Specific Populations, and Patient Counseling Information].
Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
LEVAQUIN® is indicated in pediatric patients (≥ 6 months of age) only for the prevention of inhalational anthrax (post-exposure) [see Indications and Usage]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving LEVAQUIN® [see Use in Specific Populations].
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 [see Animal Toxicology and/or Pharmacology].
Blood Glucose Disturbances
As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with LEVAQUIN®, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with LEVAQUIN®, LEVAQUIN® should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions; Drug Interactions; Patient Counseling Information].
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions ; Patient Counseling Information].
Development of Drug Resistant Bacteria
Prescribing LEVAQUIN® in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information].
USE IN SPECIFIC POPULATIONS
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 rabbitswere dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area.
There are, however, no adequate and well-controlled studies in pregnant women. LEVAQUIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Based on data on other fluoroquinolones and very limited data on LEVAQUIN®, it can be presumed that levofloxacin will be excreted in human milk. Because of the potential for serious adverse reactions from LEVAQUIN® in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions [5.9] and Animal Toxicology and/or Pharmacology].
Inhalational Anthrax (Post-Exposure)
Levofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied. The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [ see Indications and Usage, Dosage and Administration, Clinical Pharmacology and Clinical Studies ].
In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous LEVAQUIN®. Children 6 months to 5 years of age received LEVAQUIN® 10 mg/kg twice a day and children greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days.
A subset of children in the clinical trials (1340 LEVAQUIN®-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendonopathy, gait abnormality) during 60 days and 1 year following the first dose of study drug. Children treated with LEVAQUIN® had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 9.
Table 9: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial
N = 1340
|Non-FluoroquinoloneNon-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin|
N = 893
|p-value2-sided Fisher's Exact Test|
| 60 days ||28 (2.1%)||8 (0.9%)||p = 0.038|
| 1 year There were 1199 LEVAQUIN®-treated and 804 non-fluoroquinolone-treated children who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders were calculated using all reported events during the specified period for all children enrolled regardless of whether they completed the 1-year evaluation visit. ||46 (3.4%)||16 (1.8%)||p = 0.025|
Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) LEVAQUIN®-treated children and most were treated with analgesics. The median time to resolution was 7 days for LEVAQUIN®-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.
Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the LEVAQUIN®-treated and non-fluoroquinolone-treated children.
In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience [ see Adverse Reactions (6) ] may also be expected to occur in pediatric patients.
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as LEVAQUIN®. 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 LEVAQUIN® to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue LEVAQUIN® and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [ see Boxed Warning; Warnings and Precautions; and Adverse Reactions ].
In phase 3 clinical trials, 1,945 LEVAQUIN®-treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN®. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions ].
Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using LEVAQUIN® with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ].
The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology].
Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration].
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.