Levofloxacin

was 1.4 times the highest recommended human dose (750 mg) based upon relative body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of levofloxacin averaged approximately 11.8 mcg/g at C_max.

Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.

Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest recommended human dose based upon relative body surface area.

13.2 Animal Toxicology and/or Pharmacology

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.10)]. In immature dogs (4 to 5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones.

While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs.

In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release.

In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 to 19 days).

Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the levofloxacin arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or piperacillin/tazobactam (N=4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the levofloxacin arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.

Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3 to 15 after completing therapy) were 58.1% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17.2, 12]. The microbiological eradication rates at the posttherapy visit were 66.7% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 11.

14.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies are presented in Table 12.

Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae

Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2^nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 13.

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 14.

14.3 Community-Acquired Pneumonia: 5-day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 500 mg IV or orally, every day for 10 days.

Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the levofloxacin 750 mg group and 91.1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5.9, 5.4]. In the clinically evaluable population (31 to 38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding cannot be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 15.

14.4 Acute Bacterial Sinusitis: 5-day and 10 to 14 day Treatment Regimens

Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth x 5 days or 500 mg by mouth once daily x 10 to 14 days. To evaluate the safety and efficacy of a high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin 500 mg by mouth once daily for 10 days.

Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91.4% (139/152) in the levofloxacin 750 mg group and 88.6% (132/149) in the levofloxacin 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10] for levofloxacin 750 mg minus levofloxacin 500 mg).

Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day regimens at the test-of-cure visit 22 days post treatment.

14.5 Complicated Skin and Skin Structure Infections

Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 ± 4.7 days. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-treated patients and 44% of the comparator-treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication.

Among those who could be evaluated clinically 2 to 5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with levofloxacin and 106/132 (80.3%) for patients treated with the comparator.

Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.

14.6 Chronic Bacterial Prostatitis

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB₃) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5 to 18 days after completion of therapy was 75% in the levofloxacin group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 17.

Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates.

Clinical success (cure + improvement with no need for further antibiotic therapy) rates in microbiologically evaluable population 5 to 18 days after completion of therapy were 75% for levofloxacin-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24 to 45 days after completion of therapy) rates were 66.7% for the levofloxacin-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.4, 2.89] for levofloxacin minus ciprofloxacin).

14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the U.S. from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 18.

Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to levofloxacin treatment are presented in Table 19.

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen

To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the U.S. from June 1993 to January 1995 comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1 to 12 days post-therapy in patients with a pathogen identified at baseline.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.

14.9 Inhalational Anthrax (Post-Exposure)

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.13); Dosage and Administration (2.1, 2.2)].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC_0-24) is 47.5 ± 6.7 and  54.6 ± 11.1 mcg•h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].

In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk.

In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions (5.10), Use in Specific Populations (8.4)].

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD₅₀ (~2.7 x 10⁶) spores (range 17 to 118 LD₅₀) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected T_max (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC_0-24 was 33.4 ± 3.2 mcg•h/mL (range 30.4 to 36 mcg•h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher’s Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.

14.10 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.

The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.14) , Dosage and Administration (2.1) , (2.2)].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC_0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].

A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD₅₀ (range 3 to 145 LD₅₀) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30-min infusion ranged from 2.84 to 3.5 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from <0.03 to 0.06 mcg/mL. Mean (SD) AUC_0-24 was 11.9 (3.1) mcg.h/mL (range 9.5 to 16.86 mcg.h/mL). Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (≥ 39^oC for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001, Fisher’s Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.

15 REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard – 9^th ed. CLSI Document M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, 2012.
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22^nd Informational Supplement. CLSI Document M100 – S22, 2012.
• CLSI Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard – 11^th ed. CLSI M2-A11, 2012.
• CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – 2^nd ed. CLSI Document M45-A2, 2010. 

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Levofloxacin Tablets

Levofloxacin Tablets, 250 mg are terra pink colored capsule shaped, biconvex film-coated tablets, debossed with ‘13’ on one side and ‘T’ on the other side.

         Bottles of 50                             NDC 65862-536-50
         Bottles of 1000                         NDC 65862-536-99
         10 x 10 Unit-dose Tablets         NDC 65862-536-10

Levofloxacin Tablets, 500 mg are peach colored capsule shaped, biconvex film-coated tablets, debossed with ‘12’ on one side and ‘T’ on the other side.

         Bottles of 50                             NDC 65862-537-50
         Bottles of 1000                         NDC 65862-537-99
         10 x 10 Unit-dose Tablets         NDC 65862-537-10

Levofloxacin Tablets, 750 mg are white capsule shaped, biconvex film-coated tablets, debossed with ‘11’ on one side and ‘T’ on the other side.

          Bottles of 20                             NDC 65862-538-20
          Bottles of 500                           NDC 65862-538-05
          10 x 10 Unit-dose Tablets         NDC 65862-538-10

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] in well-closed containers.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide (17.6)

17.1 Antibacterial Resistance

Antibacterial drugs including levofloxacin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When levofloxacin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by levofloxacin ^{or other antibacterial drugs in the future.}

17.2 Administration with Food, Fluids, and Concomitant Medications

Patients should be informed that levofloxacin tablets may be taken with or without food. The tablet should be taken at the same time each day.

Patients should drink fluids liberally while taking levofloxacin to avoid formation of a highly concentrated urine and crystal formation in the urine.

Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral levofloxacin administration.

17.3 Serious and Potentially Serious Side Effects

Patients should be informed of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use:  

• Tendon Disorders:  Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin ^{treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.}
• Exacerbation of Myasthenia Gravis:  Patients should inform their physician of any history of myasthenia gravis. Patients should notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions:  Patients should be informed that levofloxacin can cause hypersensitivity reactions, even following the first dose. Patients should discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.  
• Hepatotoxicity:  Severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin. Patients should inform their physician and be instructed to discontinue levofloxacin treatment immediately if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.  
• Convulsions:  Convulsions have been reported in patients taking fluoroquinolones, including levofloxacin. Patients should notify their physician before taking this drug if they have a history of convulsions.  
• Neurologic Adverse Effects (e.g., dizziness, lightheadedness, increased intracranial pressure):  Patients should know how they react to levofloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Patients should notify their physician if persistent headache with or without blurred vision occurs.
• Diarrhea:  Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.  
• Peripheral Neuropathies:  Patients should be informed that peripheral neuropathy has been associated with levofloxacin use. Symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue treatment and contact their physician.  
• Prolongation of the QT Interval:  Patients should inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Patients should notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness. 
• Musculoskeletal Disorders in Pediatric Patients:  Parents should inform their child's physician if their child has a history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their child's physician of any tendon or joint-related problems that occur during or following levofloxacin ^{therapy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)].} 
• Photosensitivity/Phototoxicity:  Patients should be advised that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolone antibiotics. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors when taking fluoroquinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn like reaction or skin eruption occurs, patients should contact their physician.

17.4 Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin

Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue levofloxacin and consult a physician.

Patients should be informed that concurrent administration of warfarin and levofloxacin has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin concomitantly.

17.5 Plague and Anthrax Studies

Patients given levofloxacin for these conditions should be informed that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.

Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)
AP-509302, INDIA

Repackaged By:

ReadyMeds

Dothan, AL 36301

17.6 FDA-Approved Medication Guide

MEDICATION GUIDE
Levofloxacin Tablets

Read this Medication Guide before you start taking levofloxacin tablets and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about levofloxacin tablets?

Levofloxacin tablets, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects could result in death .

If you have any of the following serious side effects while you take levofloxacin tablets, get medical help right away. Talk with your healthcare provider about whether you should continue to take levofloxacin tablets.

1.  Tendon rupture or swelling of the tendon (tendinitis).

• Tendon problems can happen in people of all ages who take levofloxacin tablets. Tendons are tough cords of tissue that connect muscles to bones.

Some tendon problems include pain, swelling, tears, and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.

• The risk of getting tendon problems while you take levofloxacin tablets are higher if you:
  • are over 60 years of age
  • are taking steroids (corticosteroids)
  • have had a kidney, heart or lung transplant. 
• Tendon problems can happen in people who do not have the above risk factors when they take levofloxacin tablets.
• Other reasons that can increase your risk of tendon problems can include: 
  • physical activity or exercise
  • kidney failure
  • tendon problems in the past, such as in people with rheumatoid arthritis (RA) 
• Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking levofloxacin tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area.

The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of levofloxacin tablets. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.

• Tendon rupture can happen while you are taking or after you have finished taking levofloxacin tablets. Tendon ruptures have happened up to several months after people have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
  • hear or feel a snap or pop in a tendon area
  • bruising right after an injury in a tendon area
  • unable to move the affected area or bear weight

2.  Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

• See “What are the possible side effects of levofloxacin tablets?”

What are levofloxacin tablets?

Levofloxacin tablets are a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria.
These bacterial infections include:

• nosocomial pneumonia
• community-acquired pneumonia
• acute sinus infection
• acute worsening of chronic bronchitis
• skin infections, complicated and uncomplicated
• chronic prostate infection
• urinary tract infections, complicated and uncomplicated
• acute kidney infection (pyelonephritis)
• inhalational anthrax
• plague

Studies of levofloxacin tablets for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people.

Levofloxacin tablets are also used to treat children who are 6 months of age or older and may have breathed in anthrax germs, have plague, or been exposed to plague germs.

It is not known if levofloxacin tablets are safe and effective in children under 6 months of age.

The safety and effectiveness in children treated with levofloxacin tablets for more than 14 days is not known.

Who should not take levofloxacin tablets?

Do not take levofloxacin tablets if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin tablets. See the end of this leaflet for a complete list of ingredients in levofloxacin tablets.

What should I tell my healthcare provider before taking levofloxacin tablets?

Before you take levofloxacin tablets , tell your healthcare provider if you:

• have tendon problems
• have a problem that causes muscle weakness (myasthenia gravis)
• have central nervous system problems such as seizures (epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation”
• have low blood potassium (hypokalemia)
• have bone problems
• have joint problems including rheumatoid arthritis (RA)
• have kidney problems. You may need a lower dose of levofloxacin tablets if your kidneys do not work well.
• have liver problems
• have diabetes or problems with low blood sugar (hypoglycemia)
• are pregnant or plan to become pregnant. It is not known if levofloxacin tablets will harm your unborn child.
• are breastfeeding or plan to breastfeed. It is not known if levofloxacin passes into your breast milk. You and your healthcare provider should decide if you will take levofloxacin tablets or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Levofloxacin tablets and other medicines can affect each other causing side effects.

Especially tell your healthcare provider if you take: 

• a steroid medicine
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• certain medicines may keep levofloxacin tablets from working correctly. Take levofloxacin tablets either 2 hours before or 2 hours after taking these medicines or supplements:
  • an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron, or zinc
  • sucralfate (Carafate^®)
  • didanosine (Videx^®,Videx^®EC) 
• a blood thinner (warfarin, Coumadin, Jantoven)
• an oral anti-diabetes medicine or insulin
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take levofloxacin tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures.
• theophylline (Theo-24^®, Elixophyllin^®, Theochron^®, Uniphyl^®, Theolair^®)
• a medicine to control your heart rate or rhythm (antiarrhythmics)

Ask your healthcare provider if you are not sure if any of your medicines are listed above. 

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take levofloxacin tablets?

• Take levofloxacin tablets exactly as your healthcare provider tells you to take them.
• Take levofloxacin tablets at about the same time each day.
• Drink plenty of fluids while you take levofloxacin tablets.
• Levofloxacin tablets can be taken with or without food.
• If you miss a dose of levofloxacin tablets, take it as soon as you remember. Do not take more than 1 dose in 1 day.
• Do not skip any doses of levofloxacin tablets or stop taking them, even if you begin to feel better, until you finish your prescribed treatment unless:
  • you have tendon problems. See “What is the most important information I should know about levofloxacin tablets?” .
  • you have a serious allergic reaction. See “What are the possible side effects of levofloxacin tablets?”.
  • your healthcare provider tells you to stop taking levofloxacin tablets.

Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin tablets doses will help you lower the chance that the bacteria will become resistant to levofloxacin tablets. If your infection does not get better while you take levofloxacin tablets, it may mean that the bacteria causing your infection may be resistant to levofloxacin tablets. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin tablets and other similar antibiotic medicines may not work for you in the future.

• If you take too much levofloxacin, call your healthcare provider or get medical help right away.

What should I avoid while taking levofloxacin tablets?

• Levofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how levofloxacin tablets affect you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take levofloxacin tablets, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of levofloxacin tablets?

Levofloxacin tablets  can cause serious side effects, including:

• See “What is the most important information I should know about l evofloxacin tablets?”
• Serious allergic reactions.

Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction:

• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• skin rash

Skin rash may happen in people taking levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin tablets.

Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets. Call your healthcare provider right away if you have unexplained symptoms such as:

• nausea or vomiting
• stomach pain
• fever
• weakness
• abdominal pain or tenderness
• itching
• unusual tiredness
• loss of appetite
• light colored bowel movements
• dark colored urine
• yellowing of your skin or the whites of your eyes

Stop taking levofloxacin tablets and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin tablets (a liver problem).

• Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including levofloxacin tablets. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking levofloxacin tablets will change your risk of having a seizure. 

Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of levofloxacin tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: 

• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
• trouble sleeping
• nightmares
• feel lightheaded
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• a headache that will not go away, with or without blurred vision.

• Intestine infection (Pseudomembranous colitis)

Pseudomembranous colitis can happen with many antibiotics, including levofloxacin tablets. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.

• Changes in sensation and nerve damage (Peripheral Neuropathy)

Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including levofloxacin tablets. Stop levofloxacin tablets and talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:

• pain
• burning
• tingling
• numbness
• weakness

The nerve damage may be permanent.

• Serious heart rhythm changes (QT prolongation and torsades de pointes)

Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin tablets may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:

• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)

• Joint Problems

Increased chance of problems with joints and tissues around joints in children can happen. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with levofloxacin tablets.

• Changes in blood sugar

People who take levofloxacin tablets and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin tablets, stop taking levofloxacin tablets and call your healthcare provider right away. Your antibiotic medicine may need to be changed.

• Sensitivity to sunlight (photosensitivity)

See “What should I avoid while taking levofloxacin tablets?”

The most common side effects of levofloxacin tablets include:

• nausea
• headache
• diarrhea
• insomnia
• constipation
• dizziness

In children 6 months and older who take levofloxacin tablets to treat anthrax disease or plague, vomiting is also common. 

Tell your healthcare provider if you feel dizzy or faint during a treatment with levofloxacin tablets. 

Levofloxacin tablets may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test. 

These are not all the possible side effects of levofloxacin tablets. Tell your healthcare provider about any side effect that bothers you or that does not go away. 

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 

How should I store levofloxacin tablets?

• Store levofloxacin tablets at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].
• Keep levofloxacin tablets in a tightly closed container.

Keep levofloxacin tablets and all medicines out of the reach of children.

General information about the safe and effective use of levofloxacin tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin tablets for a condition for which it is not prescribed. Do not give levofloxacin tablets to other people, even if they have the same symptoms that you have. They may harm them. 

This Medication Guide summarizes the most important information about levofloxacin tablets. If you would like more information about levofloxacin tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin tablets that is written for healthcare professionals.

For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

What are the ingredients in levofloxacin tablets? 

Active ingredient: levofloxacin   

Inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, and titanium dioxide. In addition 250 mg contains iron oxide red and 500 mg contains iron oxide red and iron oxide yellow

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Aurobindo Pharma USA, Inc.2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)
AP-509302, INDIA

Repackaged By:

ReadyMeds

Dothan, AL 36301

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (7 Tablet Bottle)

NDC 64205-537-07
Once-a-day
Levofloxacin Tablets
500 mg
ATTENTION PHARMACIST: Dispense the
accompanying Medication Guide to each patient
Rx only                                          7 Tablets
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 500 mg (10 Tablets)

NDC 64205-537-10
Once-a-day
Levofloxacin Tablets
500 mg
ATTENTION PHARMACIST: Dispense the
accompanying Medication Guide to each patient
Rx only        10 Tablets
AUROBINDO