Levofloxacin Drug Information

Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague 2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric patients who weigh 30 kg or greater is described below in Table 2. levofloxacin tablets cannot be administered to patients who weigh less than 30 kg because of the limitations of the available strength. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg. Table 2 Levofloxacin Tablets Dosage in Pediatric Patients Weighing 30 kg or greater with Inhalational Anthrax (Post-Exposure) and Plague* Due to Bacillus anthracis and Yersinia pestis. Sequential therapy (intravenous levofloxacin injection to oral levofloxacin tablets) may be instituted at the discretion of the healthcare provider. Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. § The safety of levofloxacin tablets in pediatric patients for durations of therapy beyond 14 days has not been studied.

Dosage Adjustment in Adults with Renal Impairment

Administer levofloxacin tablets with caution in patients with renal impairment. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced in these patients. In patients with renal impairment (creatinine clearance less than 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance.

No adjustment is necessary for patients with a creatinine clearance greater than or equal to 50 mL/minute. Table 3 shows how to adjust dose based on creatinine clearance. Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance less than 50 mL/minute)

Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Levofloxacin tablets 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

Levofloxacin tablets can be administered without regard to food. Hydration for Patients Receiving Levofloxacin Tablets Adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones.

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: • Disabling and Potentially Irreversible Serious Adverse Reactions • Tendinitis and Tendon Rupture • Peripheral Neuropathy • Central Nervous System Effects • Exacerbation of Myasthenia Gravis • Other Serious and Sometimes Fatal Reactions • Hypersensitivity Reactions • Hepatotoxicity • Risk of Aortic Aneurysm and Dissection • Clostridium difficile-Associated Diarrhea • 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. 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 to 14 days, and the mean number of days on therapy was 10 days. 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 N = 7274 N=3758 (women) # pool of studies included IV and oral administration Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537) anemiathrombocytopenia 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 Nervous System Disorders tremorconvulsions paresthesia vertigo hypertonia hyperkinesias abnormal gait somnolence syncope gastritisstomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembranous/ C. difficile colitis Hepatobiliary Disorders abnormal hepatic functionincreased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous Tissue Disorders urticaria Musculoskeletal and Connective Tissue Disorders arthralgiatendinitis myalgia skeletal pain Renal and Urinary Disorders abnormal renal functionacute 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, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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: anaphylactic/anaphylactoid 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

Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets 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. 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

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

However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max and k e were slightly lower while T max and t1/2 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

Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin.

Probenecid and Cimetidine

No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t 1/2 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 Pregnancy Category C. Levofloxacin was not teratogenic in rats at doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended oral 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 oral 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.

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 (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. 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. Safety and effectiveness of levofloxacin in pediatric patients below the age of six months have not been established. Pharmacokinetics following intravenous administration 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. Dosage in Pediatric Patients with Inhalational Anthrax or Plague For the recommended levofloxacin tablet dosage in pediatric patients with inhalational anthrax or plague, see Dosage and Administration. Levofloxacin Tablets cannot be administered to pediatric patients who weigh less than 30 kg because of the limitations of the available strengths.

Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg. Adverse Reactions In clinical trials, 1534 pediatric patients (6 months to 16 years of age) were treated with oral and intravenous levofloxacin. Levofloxacin tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths.

A subset of pediatric patients in the clinical trials (1340 levofloxacin-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, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Pediatric patients treated with levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients 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. No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.

Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the levofloxacin-treated and non-fluoroquinolone-treated pediatric patients. In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience may also be expected to occur in pediatric patients.

Levofloxacin tablets are contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials. Known hypersensitivity to levofloxacin or other quinolones

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.