LEVAQUIN Film-coated tablet Ref.[49676] Active ingredients: Levofloxacin

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)].

5.2 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including LEVAQUIN, 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 LEVAQUIN in patients with a known history of myasthenia gravis [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].

5.3 Hypers ensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including LEVAQUIN . These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. LEVAQUIN should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions (6); Patient Counseling Information (17.3)].

5.4 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 (6); Patient Counseling Information (17.3)].

5.5 Hepatotoxicity

Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with LEVAQUIN No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.4)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6); Patient Counseling Information (17.3)].

5.6 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 (17.3)].

5.7 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 (6.2), Patient Counseling Information (17.3)].

5.8 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 LEVAQUIN . LEVAQUIN should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition [see Adverse Reactions (6), Patient Counseling Information (17.3)].

5.9 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 (6.3), Use in Specific Populations (8.5), and Patient Counseling Information (17.3)].

5.10 Mus culoskeletal 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 (1.13)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving LEVAQUIN [see Use in Specific Populations (8.4)].

In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].

5.11 Blood Glucos e 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 (6.2); Drug Interactions (7.3); Patient Counseling Information (17.4)].

5.12 Photos ensitivity / 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 involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].

5.13 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 (17.1)].

6.1 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 [see Warnings and Precautions (5.1)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.4)]
• Hepatotoxicity [see Warnings and Precautions (5.5)]
• Central Nervous System Effects [see Warnings and Precautions (5.6)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]
• Peripheral Neuropathy [see Warnings and Precautions (5.8)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.9)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.10)]
• Blood Glucose Disturbances [see Warnings and Precautions (5.11)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.12)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.13)]

Hypotension has been associated with rapid or bolus intravenous infusion of LEVAQUIN. LEVAQUIN should be infused slowly over 60 to 90 minutes, depending on dosage [see Dosage and Administration (2.5)].

Crystalluria and cylindruria have been reported with quinolones, including LEVAQUIN. Therefore, adequate hydration of patients receiving LEVAQUIN should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to LEVAQUIN in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was <65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with LEVAQUIN for a wide variety of infectious diseases [see Indications and Usage (1)]. Patients received LEVAQUIN doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3-14 days, and the mean number of days on therapy was 10 days.

The overall incidence, type and distribution of adverse reactions was similar in patients receiving LEVAQUIN doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of LEVAQUIN due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).

Adverse reactions occurring in ≥1% of LEVAQUIN -treated patients and less common adverse reactions, occurring in 0.1 to <1% of LEVAQUIN-treated patients, are shown in Table 6 and Table 7, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table 6. Common (≥1%) Adverse Reactions Reported in Clinical Trials with
LEVAQUIN:

^* N=7274
^† N=3758 (women)

Table 7. Less Common (0.1 to 1%) Advers e Reactions Reported in Clinical Trials with LEVAQUIN (N=7537):

^* 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 LEVAQUIN. The relationship of the drugs to these events is not presently established.

Table 8 lists adverse reactions that have been identified during post-approval use of LEVAQUIN. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 8. Postmarketing Reports Of Advers e Drug Reactions:

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

LEVAQUIN Tablets and Oral Solution

While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of LEVAQUIN Tablets and Oral Solution with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral LEVAQUIN administration.

LEVAQUIN Injection

There are no data concerning an interaction of intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins, didanosine, or metal cations. However, no fluoroquinolone should be coadministered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.5)].

7.2 Warfarin

No significant effect of LEVAQUIN on the peak plasma concentrations, AUC, and other disposition parameters for R- and S-warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that LEVAQUIN enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and LEVAQUIN use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if LEVAQUIN is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3); Patient Counseling Information (17.4)].

7.3 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 [see Warnings and Precautions (5.11); Adverse Reactions (6.2), Patient Counseling Information (17.4)].

7.4 Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including LEVAQUIN, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions (5.6)].

7.5 Theophylline

No significant effect of LEVAQUIN on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when LEVAQUIN is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions (5.6)].

7.6 Cyclosporine

No significant effect of LEVAQUIN on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when coadministered with some other fluoroquinolones. Levofloxacin C and k were slightly lower while T and t were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication. The differences, however, are not considered to be clinically significant. Therefore, no dosage adjustment is required for LEVAQUIN or cyclosporine when administered concomitantly.

7.7 Digoxin

No significant effect of LEVAQUIN on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for LEVAQUIN or digoxin is required when administered concomitantly.

7.8 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 t of levofloxacin were higher while CL/F and CL were lower during concomitant treatment of LEVAQUIN with probenecid or cimetidine compared to LEVAQUIN alone. However, these changes do not warrant dosage adjustment for LEVAQUIN when probenecid or cimetidine is co-administered.

7.9 Interactions with Laboratory or Diagnostic Testing

Some fluoroquinolones, including LEVAQUIN, 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. 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 (5.10) and Animal Toxicology and/or Pharmacology (13.2)].

Inhalational Anthrax (Post-Exposure)

Levofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied. The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Indications and Usage (1.13), Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.9)].

Adverse Events

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-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 LEVAQUIN had a significantly higher incidence of musculoskeletal disorders when compared to the nonfluoroquinolone-treated children as illustrated in Table 9.

Table 9. Incidence of Mus culoskeletal Disorders in Pediatric Clinical Trial:

^* Non-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin
^† 2-sided Fisher’s Exact Test
^‡ There were 1199 LEVAQUIN-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%) 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 (5.1); and Adverse Reactions (6.3)].

In phase 3 clinical trials, 1,945 LEVAQUIN -treated patients (26%) were ≥65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.5)].

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using LEVAQUIN with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.9)].

The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance <50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of LEVAQUIN are not required following hemodialysis or CAPD [see Dosage and Administration (2.3)].

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.