Clarithromycin Extended-release Research Articles

A prospective, double-blind, multicenter study comparing clarithromycin extended-release with trovafloxacin in patients with community-acquired pneumonia

Background: Treatment guidelines for community-acquired pneumonia (CAP) generally include use of a macrolide, a fluoroquinolone, or doxycycline, although there is some debate concerning the use of a fluoroquinolone. Objective: The efficacy and tolerability of a new once-daily, extended-release (ER) formulation of clarithromycin were compared with those of a fluoroquinolone, trovafloxacin, in the treatment of patients with CAP. Methods: This was a prospective, multicenter, double-blind, double-dummy, parallel-group trial in which outpatients were randomized to receive 7 days of once-daily treatment with either clarithromycin ER (two 500-mg tablets) or trovafloxacin (200 mg). Eligible patients were ≥18 years old with signs and symptoms of pneumonia, radiologic evidence of an acute infiltrate, and mild to moderate infection, as classified by the investigator. Results: One hundred seventy-six patients were randomized to study treatment. They were primarily white (88%) and equally distributed between the sexes (52% female). Their mean (±SD) age was 47.5 ± 16.2 years. Results were similar between treatment groups in rates of clinical cure, microbiologic cure, bacteriologic eradication, and radiologic success at the test-of-cure visit (14–21 days posttreatment) for both the per-protocol and intent-to-treat analyses. Among clinically evaluable patients, clinical cure rates for clarithromycin ER and trovafloxacin were 87% ( 74 85 ) and 95% ( 63 66 ), respectively, and radiologic success rates were 95% ( 80 84 ) and 95% ( 63 66 ), respectively. There were no statistically significant differences between groups. In clinically and microbiologically evaluable patients, overall bacteriologic eradication rates were 89% ( 85 95 ) for clarithromycin ER and 96% ( 64 67 ) for trovafloxacin, with no significant differences between groups. Both antibiotics demonstrated high eradication rates against target microorganisms. There were no clinically meaningful differences in the incidence of specific drug-related adverse events. The majority of drug-related adverse events (>90%) were considered mild or moderate and resolved without the need for additional treatment. Conclusions: Although the study was prematurely terminated, resulting in inadequate power to demonstrate equivalence, once-daily clarithromycin ER was effective and well tolerated in the treatment of ambulatory adult (age ≥18 years) outpatients with CAP.

Extended-release clarithromycin: efficacy against pneumonia

Extended-release clarithromycin: efficacy against pneumonia

Pharmacokinetics and tolerability of extended-release clarithromycin

Background: Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive, gram-negative, and atypical respiratory tract and skin/skin structure pathogens, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of Mycobacterium avium complex infection and peptic ulcers due to H pylori. Objective: In this article, we review the results of 3 studies of the steady-state pharmacokinetic profiles of clarithromycin and 14( R)-hydroxy-clarithromycin after multiple oral once-daily doses of 500-mg extended-release (ER) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithromycin conducted in adults with acute maxillary sinusitis (AMS) and acute exacerbation of chronic bronchitis (AECB). Methods: In the 3 pharmacokinetic studies, multiple-dose regimens of clarithromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and female volunteers, were evaluated. The effect of administration in nonfasting versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studies conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin tablets twice daily or 1000 mg (2 × 500 mg) ER clarithromycin tablets once daily for 7 days (AECB) or 14 days (AMS). Results: Bioavailability of the ER clarithromyin tablet administered with food was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and active metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting conditions. Compared with the IR tablet, administration of the ER tablet resulted in significantly lower ( P < 0.05) clarithromycin peak plasma concentration (C max), delayed time to C max, and lower degree of concentration fluctuation, confirming its in vivo extended-release characteristics. The most frequently reported adverse events (AEs) in the phase III clinical trials were diarrhea, abnormal taste, and nausea and were generally mild or moderate. The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation ( P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste ( P = 0.004). Conclusions: The results from the 3 pharmacokinetic studies reviewed demonstrate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials. The ER tablet should be taken with food to maximize bioavailability. The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.

Comparison of the efficacy of extended-release clarithromycin tablets and amoxicillin/clavulanate tablets in the treatment of acute exacerbation of chronic bronchitis

Background: Clarithromycin has established efficacy and safety in the treatment of respiratory infections. Objective: This study examined the efficacy and safety of a new extended-release formulation of clarithromycin compared with amoxicillin/clavulanate in the treatment of acute exacerbation of chronic bronchitis (AECB). Methods: This phase IIIB, multicenter, randomized, parallel-group, investigator-blinded study in patients with AECB and productive cough with purulent sputum compared treatment with extended-release clarithromycin (two 500-mg tablets once daily for 7 days) and amoxicillin/clavulanate (one 875-mg tablet twice daily for 10 days). Assessments were performed before treatment, between study days 10 and 12 (or within 48 hours after premature discontinuation), and between study days 17 and 21 (test of cure). Results: Of 287 patients randomized and treated, 270 were clinically evaluable (137 clarithromycin, 133 amoxicillin/clavulanate). Treatment groups were well matched in terms of demographic characteristics, medical condition, and history. Among clinically evaluable patients at test of cure, 85% and 87% of clarithromycin- and amoxicillin/clavulanate-treated patients, respectively, demonstrated clinical cure (as defined in 1998 draft US Food and Drug Administration guidelines); among clinically and bacteriologically evaluable patients, 92% versus 89%, respectively, demonstrated bacteriologic cure. Overall pathogen eradication rates were similar in the 2 groups (88% clarithromycin, 89% amoxicillin/clavulanate). Rates of premature discontinuation of study drug for any reason differed between treatments: 3% ( 4 142 ) of clarithromycin-treated patients versus 12% ( 17 145 ) of amoxicillin/clavulanate-treated patients ( P = 0.005). One percent ( 2 142 ) and 6% ( 8 145 ) of the respective treatment groups discontinued study drug because of adverse events. Adverse events generally occurred with a similar frequency in the 2 groups; however, taste alteration was more common with clarithromycin ( 9 142 [6%]) than with amoxicillin/clavulanate ( 1 145 [1%]; P = 0.01). Mean severity scores for gastrointestinal adverse events showed a significant difference between groups (1.16 for clarithromycin-treated patients and 1.58 for amoxicillin/clavulanate-treated patients; P = 0.016). Conclusions: The results of this study demonstrate the clinical and bacteriologic equivalence and improved gastrointestinal tolerability of a 7-day course of once-daily extended-release clarithromycin relative to a 10-day course of twice-daily amoxicillin/clavulanate in the treatment of AECB.

Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of adult patients with acute maxillary sinusitis

Background: Clarithromycin has an established bacteriologic efficacy and safety profile in the treatment of respiratory tract infections. Objective: This study compares the efficacy and tolerability of extended-release and immediate-release formulations of clarithromycin in patients with acute maxillary sinusitis. Methods: Fourteen days' treatment with once-daily clarithromycin was compared with the immediate-release, twice-daily formulation in a phase III, randomized, double-blind, parallel-group, multicenter study. Patients aged ≥12 years with signs, symptoms, and a radiologically confirmed diagnosis of acute maxillary sinusitis were eligible. Patients were assessed before treatment, within 48 hours after treatment, on study days 16 to 18, and at the test-of-cure visit on study days 24 to 31. Patients who received ≥1 dose of study drug were included in the safety analysis. Results: Of 283 patients treated, 245 were included in the efficacy analysis (122 in the extended-release group, 123 in the immediate-release group). Treatment groups were well matched with respect to demographic characteristics and medical condition and history. At the test-of-cure visit, 85% of patients in the clarithromycin extended-release group and 79% in the immediate-release group were deemed clinical cures; 89% and 91% in the extended-release and immediate-release groups, respectively, demonstrated radiographic success. Overall incidences of study drug-related adverse events were similar in the 2 treatment groups (32% in the extended-release group and 28% in the immediate-release group); however, significantly fewer patients receiving extended-release clarithromycin ( 2 142 [1%]), compared with those receiving the immediate-release formulation ( 10 141 [7%]; P = 0.02) discontinued therapy because of drug-related gastrointestinal symptoms or abnormal taste. No clinically meaningful changes in laboratory values or vital signs were observed during the study. Conclusion: Although the efficacy of the 2 formulations was comparable, once-daily clarithromycin extended-release was better tolerated than the twice-daily immediate-release formulation by patients with acute maxillary sinusitis.

Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of patients with acute exacerbation of chronic bronchitis

Background: Clarithromycin has an established efficacy and safety profile in the treatment of respiratory tract infections. Objective: The purpose of this study was to compare the clinical and bacteriologic efficacy and tolerability of clarithromycin extended-release and immediate-release formulations in patients with acute exacerbation of chronic bronchitis (AECB). Methods: In a phase III, randomized, double-blind, parallel-group, multicenter study, patients aged ≥12 years with signs and symptoms of AECB and a productive cough with purulent sputum received treatment with extended-release (two 500-mg tablets once daily) or immediate-release (one 500-mg tablet twice daily) clarithromycin for 7 days. Assessments were performed before treatment, within 48 hours after treatment, and at the test-of-cure visit (study days 19–21). Patients who took ≥1 dose of study drug were included in the safety analysis. Results: Of 620 patients randomized and treated, 182 were clinically and bacteriologically assessable (100 in the extended-release group and 82 in the immediate-release group). Treatment groups were well matched with respect to demographic characteristics and medical and social history. At the test-of-cure visit, 83% ( 83 100 ) of patients in the extended-release and 82% ( 67 82 ) of patients in the immediate-release group achieved clinical cure; 86% ( 85 99 ) and 85% ( 70 82 ), respectively, demonstrated bacteriologic cure. Overall pathogen eradication rates were 86% ( 100 116 ) in the extended-release group and 88% ( 86 98 ) in the immediate-release group. The most frequently reported adverse events were diarrhea (6% in extended-release group vs 4% in immediate-release group; no significant difference), taste alterations (4% in each group), and nausea (3% in each group); no clinically meaningful changes in laboratory values or vital signs, as assessed by the investigator, were observed. Conclusion: This study suggests that clarithromycin extended-release and immediate-release formulations have equivalent clinical and bacteriologic efficacy and tolerability in patients with AECB.