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.

Clinical Studies

Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous LEVAQUIN® (750 mg once daily) followed by oral LEVAQUIN® (750 mg once daily) for a total of 7-15 days to intravenous imipenem/cilastatin (500-1000 mg every 6-8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7-15 days. LEVAQUIN®-treated patients received an average of 7 days of intravenous therapy (range: 1-16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1-19 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 LEVAQUIN® arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the LEVAQUIN® 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 LEVAQUIN® 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 LEVAQUIN® 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 3-15 after completing therapy) were 58.1% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-17.2, 12.0]. The microbiological eradication rates at the posttherapy visit were 66.7% for LEVAQUIN® and 60.6% for comparator. The 95% CI for the difference of eradication rates (LEVAQUIN® minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen are detailed in Table 12.

Table 12: Clinical Success Rates and Microbiological Eradication Rates (Nosocomial Pneumonia)

Community-Acquired Pneumonia: 7-14 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 LEVAQUIN® 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 LEVAQUIN® 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 (LEVAQUIN® minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg LEVAQUIN® 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 13.

Table 13: Microbiologic Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies

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

LEVAQUIN® was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥ 2µg/ml), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95.0%) achieved clinical and bacteriologic success at post-therapy. The clinical and bacterial success rates are shown in Table 14.

Table 14: Clinical and Bacterial Success Rates for LEVAQUIN®-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy)

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 15.

Table 15: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)

Community-Acquired Pneumonia: 5-Day Treatment Regimen

To evaluate the safety and efficacy of higher dose and shorter course of LEVAQUIN®, 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 LEVAQUIN® 750 mg, IV or orally, every day for five days or LEVAQUIN® 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 LEVAQUIN® 750 mg group and 91.1% in the LEVAQUIN® 500 mg group. The 95% CI for the difference of response rates (LEVAQUIN® 750 minus LEVAQUIN® 500) was [-5.9, 5.4]. In the clinically evaluable population (31-38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the LEVAQUIN® 750 mg group and 2 out of 147 patients in the LEVAQUIN® 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 16.

Table 16: Microbiological Eradication Rates (Community-Acquired Pneumonia)

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

LEVAQUIN® is approved for the treatment of acute bacterial sinusitis (ABS) using either 50 mg by mouth x 5 days or 500 mg by mouth once daily x 10-14 days. To evaluate the afety and efficacy of a high dose short course of LEVAQUIN®, 780 outpatient adults with linically and radiologically determined acute bacterial sinusitis were evaluated in a ouble-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg y mouth once daily for five days to LEVAQUIN® 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 LEVAQUIN® 750 mg group and 88.6% (132/149) in the LEVAQUIN® 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10.0] for LEVAQUIN® 750 mg minus LEVAQUIN® 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.

Table 17: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis)

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 LEVAQUIN® 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 LEVAQUIN® and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the LEVAQUIN®-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 2-5 days after completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with LEVAQUIN® 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.

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 LEVAQUIN® 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 LEVAQUIN® and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5-18 days after completion of therapy was 75.0% in the LEVAQUIN® group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for LEVAQUIN® minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented in Table 18.

Table 18: Microbiological Eradication Rates (Chronic Bacterial Prostatitis)

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 5-18 days after completion of therapy were 75.0% for LEVAQUIN®-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for LEVAQUIN® minus ciprofloxacin). Clinical long-term success (24-45 days after completion of therapy) rates were 66.7% for the LEVAQUIN®-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for LEVAQUIN® minus ciprofloxacin).

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 LEVAQUIN®, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing LEVAQUIN® 750 mg i.v. or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg i.v. 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 LEVAQUIN® and 5 to 9 days after the last dose of active ciprofloxacin.

The bacteriologic cure rates overall for LEVAQUIN® 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 19.

Table 19: Bacteriologic Eradication at Test-of-Cure

Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to LEVAQUIN® treatment are presented in Table 20.

Table 20: Microbiological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to LEVAQUIN® 750 mg QD for 5 Days Treatment

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 LEVAQUIN®, 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 US from June 1993 to January 1995 comparing LEVAQUIN® 250 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 1-12 days post-therapy in patients with a pathogen identified at baseline.

The bacteriologic cure rates overall for LEVAQUIN® 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 21.

Table 21: Bacteriologic Eradication Overall (cUTI or AP) at Test-Of-Cure^a

Inhalational Anthrax (Post-Exposure)

The effectiveness of LEVAQUIN® for this indication is based on plasma concentrations achieved in humans, a surrogate marker considered likely to predict efficacy. LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of LEVAQUIN® associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult patients receiving oral and intravenous regimens [see INDICATIONS; DOSAGE AND ADMINISTRATION].

Levofloxacin pharmacokinetics were evaluated in various populations. Levofloxacin plasma concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication. The mean (±s.d.) steady-state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.1 ± 0.8 and 6.2 ± 1.0 µg/mL, respectively; and the corresponding total exposure is 47.9 ± 6.8 and 48.3 ± 5.4 µg·h/mL, respectively.

In adults, the safety of LEVAQUIN® 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 LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk.

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD₅₀ (~2.7 X 10⁶) spores (range 17 - 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 µg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 µg/mL. Mean steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 µg/mL. Mortality due to anthrax for animals that received a 30 day regimen of oral LEVAQUIN® 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.

REFERENCES

1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard – Seventh Edition. Clinical and Laboratory Standards Institute document M7-A7, Vol. 26, No. 2, CLSI, Wayne, PA, January 2006.

2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard – Ninth Edition. Clinical and Laboratory Standards Institute document M2-A9, Vol. 26, No. 1, CLSI, Wayne, PA, January 2006.

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