Tear concentration and safety of levofloxacin ophthalmic solution 1.5% compared with ofloxacin ophthalmic solution 0.3% after topical administration in healthy adult volunteers.

PURPOSE: This study evaluated the tear concentration and safety of levofloxacin ophthalmic solution 1.5%. METHODS: Healthy adult volunteers (N = 125) received a single initial two-drop bilateral dose of either levofloxacin 1.5% (n = 100) or ofloxacin 0.3% (n = 25). Tear-fluid drug concentrations were measured at 15 minutes and at 2, 6, 12, and 24 hours after dosing. Subjects were dosed every 2 hours while awake and 4 and 6 hours after retiring (Days 1-3) and four times daily while awake (Days 4-14). Final measurements and evaluations were done on Day 15. Tear concentrations were determined by high-performance liquid chromatography. Safety and tolerability parameters included visual acuity, ophthalmoscopy, biomicroscopy, rose bengal staining, and adverse effects. RESULTS: Tear concentrations after a single two-drop dose of levofloxacin 1.5% and ofloxacin 0.3% were above 2 microg/mL, a concentration that exceeds the minimum inhibitory concentration90 for levofloxacin in typical ocular bacterial pathogens at all time points through 24 hours. The area under the curve for the first 12 hours for levofloxacin 1.5% was 2703.5 +/- 574.22 microg.h/mL and 414.1 +/- 1179.00 microg.h/mL with ofloxacin 0.3%. Maximal concentrations were 806.9 +/- 8.57 and 73.3 +/- 165.46 microg/mL, respectively. Levofloxacin 1.5% and ofloxacin 0.3% did not differ in adverse event incidence, except for transient mild/moderate dysgeusia (14% of levofloxacin-treated subjects versus 4% of ofloxacin-treated subjects). No corneal epithelial damage or inflammatory changes were associated with levofloxacin. CONCLUSION: A single dose of levofloxacin 1.5% produced tear fluid concentrations that were well above the minimum inhibitory concentration90 for typical ocular pathogens and was safe and well tolerated.

Nebulized formoterol fumarate: Dose selection and pharmacokinetics.

To determine a dose of nebulized formoterol fumarate inhalation solution (FFIS) comparable to that of the marketed formoterol fumarate dry powder inhaler (FA, 12microg), two crossover studies were conducted in subjects with COPD. Study 1 was a single-dose, double-blind, double-dummy dose-ranging study in which 47 subjects were randomly assigned to treatment sequences that evaluated the bronchodilatory effects of FFIS 2.5, 5, 10, 20, and 40microg, FA, and placebo over 12h. Mean FEV(1) AUC(0-12) following FFIS treatment ranged from 1.3 to 3.0l/h in a dose-related manner, with equivalent values (2.3l/h) for FFIS 20microg and FA. Results for other spirometric measures, including peak and trough FEV(1) and absolute change in FEV(1) by timepoint, confirmed the comparability of FFIS 20microg and FA. Study results with the nebulized formulation supported the rapid time to onset of bronchodilation with FFIS 20microg (3.9 and 2.2min imputed for 15% and 12%/200ml response, respectively). Study 2, a single-dose, open-label crossover study, was conducted to establish the pharmacokinetic (PK) profile of nebulized formoterol and confirm comparability to FA. Thirteen subjects were randomly assigned to treatment sequences with FFIS 10, 20, and 244microg and FA with a 5-14-day washout period between each treatment. Formoterol levels were assessed from blood and urine collected pre-dose and over a 24-36-h period after dosing. Pharmacodynamic (PD) measures included clinical laboratory and ECG measures pre-dose and over a 24-h period post-dose. FFIS 244mug was rapidly absorbed with a T(max) of 12min and t(1/2) of 6.1h. Data from other doses were sporadic due to assay sensitivity. The mean amount excreted (Ae) in urine suggested linear kinetics and confirmed the comparability of FFIS 20microg and FA. Mean serum potassium decreased and mean serum glucose increased transiently in a dose-dependent manner following treatment. No clinically significant ECG changes were observed; mean heart rate increased after treatment with FFIS 244mug by up to 6bpm. Findings from dose-ranging and PK/PD studies confirmed that a 20microg dose of FFIS was comparable to formoterol fumarate delivered by dry powder inhalation (12microg) and established the dose proportionality and linear kinetics of formoterol fumarate delivered by nebulization.

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients.

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.

Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial.

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. George's Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.

Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double- blind, double-dummy, placebo- and active-controlled trial.

BACKGROUND: Recently, there have been concerns about the tolerability of long-acting (2)-agonists, including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease (COPD), who are at elevated risk for cardiovascular disease. OBJECTIVE: The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution. METHODS: Cardiac safety was assessed as part of a 12-week, randomized, double-blind, double-dummy, placebo- and active-controlled trial that was conducted at 38 centers across the United States. Male and female patients aged >/=40 years with COPD and without other significant disease were enrolled. After a 4- to 14-day, single-blind placebo run-in period, patients with COPD were randomly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer (FFIS group), formoterol fumarate 12 microg BID via dry powder inhaler (FA group), or placebo. Cardiac effects-measured by changes in heart rate (HR) and ventricular premature beats; incidence of proarrhythmic events; change in corrected QT (QTc) interval; and incidence of maximum mean change in QTc >/=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks; 12-lead electrocardiography at screening and weeks 4, 8, and 12; and patient diary cards. RESULTS: A total of 351 patients with COPD were randomized (mean age, 62.8 years; 56.1% male; mean postbronchodilator forced expiratory volume in 1 second, 1.5 L). Holter monitoring found no clinically meaningful effects of FFIS or FA treatment on mean or maximum HR, ventricular premature beats, or inci dence of arrhythmic events compared with placebo. At week 12, mean (SD) changes from baseline in mean HR were -0.6 (10.9), +0.1 (11.6), and -1.4 (9.4) bpm in the FFIS, FA, and placebo groups, respectively. The incidence of mean maximum changes in QTc >/=60 ms at any time during the 12-week treatment period were 1.6%, 1.8%, and 1.8% with FFIS, FA, and placebo, respectively. Treatment-emergent cardiac adverse events (AEs) occurred in 4.1%, 3.5%, and 4.4% of patients in the FFIS, FA, and placebo groups; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group. No deaths or serious cardiac AEs occurred during the treatment period. CONCLUSION: In this COPD population, no clinically significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution.

Efficacy and safety of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis in pediatric patients.

PURPOSE: To compare the efficacy and safety of 0.5% levofloxacin ophthalmic solution (Quixin; Santen, Napa, CA) with 0.3% ofloxacin (Ocuflox; Allergan Inc., Irvine, CA) and placebo for the treatment of pediatric bacterial conjunctivitis. METHODS: This study was a subset analysis of 167 pediatric patients (age range, 1 to 16 years) from two randomized, double-masked, multicenter, parallel group studies. Eye drops were instilled every 2 hours on days 1 and 2 and every 4 hours on days 3 through 5. Ocular signs and symptoms were noted, and conjunctival cultures were obtained on day 1 (baseline), days 3 to 5 (interim), and days 6 to 10 (final). Endpoint was defined as the last evaluable observation. Microbial and clinical outcomes were based on culture results and cardinal signs, respectively. RESULTS: At endpoint (mean of 6.5 days for 118 evaluable patients), 0.5% levofloxacin treatment demonstrated greater microbial eradication rates (percentage of patients with absence of causative organisms cultured at baseline) compared with 0.3% ofloxacin or placebo. In children age 2 to 11 years, this finding was statistically significant in favor of 0.5% levofloxacin (87% vs 62% with 0.3% ofloxacin [P < or =.032] and 88% vs 24% with placebo [P <.001]). No significant differences between treatment groups in microbial eradication rates were noted in other age subgroups. CONCLUSIONS: After 5 days of therapy, 0.5% levofloxacin ophthalmic solution was found to be safe and effective in treating pediatric bacterial conjunctivitis. Treatment with 0.5% levofloxacin achieved microbial eradication rates in children that were statistically superior to those attained with 0.3% ofloxacin or placebo.