An evaluation of comparative treatment effects with high and low dose fluticasone propionate/formoterol combination in asthma.

BACKGROUND: Despite extensive use of inhaled corticosteroid/long-acting ß2-agonist combinations in asthma, limited data evaluating dose-response for this combination class are available. The benefits of dose escalation and nature of patient subgroups likely to benefit are thus ill-defined. METHOD: In this randomised, double-blind, 8-week study the effects of two dose levels (100/10 and 500/20 µg b.i.d.) of a fixed combination of fluticasone/formoterol (flutiform(®)) were compared in 309 patients. Treatment effects upon spirometric and symptom-based endpoints were examined in the overall population and in two subgroups defined a priori by % predicted FEV1 at baseline (≥40-≤60% ["severe" airways obstruction] and >60-≤80% ["moderate" airways obstruction]). RESULTS: No dose-response was evident for spirometric outcomes (FEV1, FEV1 AUC0-12, PEFR) either overall or in either subgroup. At variance with the spirometric data, statistically significant dose-dependent differences were seen for nocturnal outcomes and consistent numerical differences were found across multiple symptom-based outcomes (symptom scores, sleep scores, rescue medication use, asthma control days, AQLQ scores, exacerbations); greater effects were noted with the higher dose of fluticasone/formoterol. Between-group differences for the overall population were driven by treatment effect differences in the "severe" subgroup. CONCLUSION: In this exploratory comparison a high dose of fluticasone/formoterol in asthmatic patients appears to provide additional improvement in symptom-based rather than spirometric outcomes. Additional benefits from high versus low dose treatment are most likely in patients with severe airway obstruction, although the doses at which ceiling effects are attained may vary between individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00734318; EudraCT number: 2007-001633-34.

Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/antagonist prolonged-release combination in healthy adult volunteers.

BACKGROUND: There is an increasing body of evidence supporting the need for prophylactic management of the adverse events (AEs) associated with long-term opioid use in patients with chronic pain. Symptoms of bowel dysfunction, such as constipation, may have a significant impact on a patient's quality of life and willingness to continue opioid therapy, and therefore should be managed proactively to ensure that the patient can continue effective pain management. The fixed-dose combination (FDC) prolonged-release (PR) oxycodone/naloxone (OXN) may be an effective therapeutic approach to delivering analgesia, with a reduced risk for opioid-induced constipation. OBJECTIVE: The aim of this paper was to report the pharmacokinetic results from a single-dose study and a multiple-dose bioequivalence study of OXN versus separate formulations of oxycodone PR and naloxone PR administered concurrently in healthy subjects. METHODS: Both studies were open-label, randomized crossover studies in healthy adult male and female subjects. In the single-dose study, subjects were randomly assigned to 1 of 4 treatment groups: OXN FDC (44 x 10/55-mg, 2 x 20/110-mg, or 1 x 40/20-mg dose strength [each given at a total combined dose of 40/220 mg]) or oxycodone PR 40 mg + naloxone PR 20 mg given in separate formulations. In the multiple-dose study, 34 subjects were randomly assigned to 1 of 3 treatment groups: OXN FDC 40/20 mg, oxycodone PR 40 mg, or naloxone PR 20 mg. Treatments were considered bioequivalent if the 90% CIs for relative bioavailability calculations fell within a predetermined range of 80% to 125%. AEs were assessed by the investigator at each study visit. RESULTS: The single-dose study included 28 subjects (22 men, 6 women; mean [SD] age, 32.3 [5.44] years; weight, 75.5 [9.3] kg; and body mass index [BMI], 24.2 [2.5] kg/mm(2)). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 473.49 (72.16), 491.22 (82.18), 488.89 (91.04), and 502.28 (84.13) ng . h/mL, respectively; mean C(max) values were 34.91 (4.36), 35.73 (4.93), 34.46 (5.03), and 40.45 (4.71) ng/mL. For naloxone-3-glucuronide (the primary analyte of naloxone), the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 539.93 (142.24), 522.45 (128.57), 520.10 (133.18), and 523.37 (119.75) ng . h/mL, respectively; mean C(max) values were 62.01 (15.96), 63.62 (19.51), 61.95 (18.37), and 63.55 (16.75) ng/mL. There were no statistically significant differences between the treatments, and each of the treatment comparisons resulted in 90% CIs within the range for bioequivalence. The multiple-dose steady-state bioequivalence study included 34 subjects (28 men, 6 women; mean [SD] age, 36 [9.4] years; weight,78.9 [11.7] kg; and BMI, 24.6 [1.9] kg/m(2)). No significant differences were observed between the treatments, with the exception of naloxone-3-glucuronide C(min,ss) values. Mean C(min,ss) values of 22.6 and 24.0 ng/mL were obtained for the OXN combination and naloxone PR tablet, respectively. In the multiple-dose study, the most frequently reported AEs with OXN,oxycodone PR, and naloxone PR were headache (7%, 26%, and 17%, respectively), anorexia (10%, 16%, and 13%), and nausea (10%, 13%, and 7%). CONCLUSIONS: The results from the single-dose study were consistent with the regulatory definition of bioequivalence of the FDCs and single components across the range of doses administered. The pharmacokinetic properties of the OXN FDC were similar to those of oxycodone PR + naloxone PR given as separate formulations, based on the regulatory definition. These findings were consistent with the results of the multiple-dose steady-state bioequivalence study. In this population of healthy volunteers, the pharmacokinetic properties of oxycodone apparently were not significantly influenced by administering oxycodone in a combination product, and the availability of naloxone-3-glucuronide from OXN was similar to that from the naloxone PR tablet. These findings suggest that the coadministration of oxycodone PR and naloxone PR in an FDC would not significantly affect the bioavailability of either of its constituents in these subjects.

Long-Term Fluticasone Propionate/Formoterol Fumarate Combination Therapy Is Associated with a Low Incidence of Severe Asthma Exacerbations.

BACKGROUND: A primary goal of asthma management is the reduction of exacerbation risk. We assessed the occurrence of oral corticosteroid-requiring exacerbations (OCS exacerbations) with long-term fluticasone/formoterol therapy, and compared it with the occurrence of similar events reported with other inhaled corticosteroid/long acting ß2-agonist (ICS/LABA) combinations. METHODS: The occurrence of OCS exacerbations was assessed in two open-label trials of fixed-dose fluticasone/formoterol administered for between 26 to 60 weeks in adults and adolescents with asthma. The incidence of OCS exacerbations with fluticasone/formoterol was compared with those reported in three recent Cochrane meta-analyses of other ICS/LABAs. RESULTS: The pooled incidence of OCS exacerbations with long-term fluticasone/formoterol was 2.1% (95% CI: 1.1, 3.2%, n/N = 16/752). In only two of the nineteen treatment arms summarized by Cochrane did OCS exacerbation incidence approximate that seen in the two fluticasone/formoterol trials (single-inhaler fluticasone/salmeterol [2.9%]; separate inhaler budesonide, beclometasone, or flunisolide plus formoterol [3.4%]). In Lasserson's review the pooled incidence of OCS exacerbations for single-inhaler combinations was 9.5% (95% CI: 8.4, 10.6%; n/N = 239/2516) for fluticasone/salmeterol, and 10.6% (95% CI: 9.3, 11.8%; n/N = 257/2433) for budesonide/formoterol. In Ducharme's and Chauhan's meta-analyses (primarily incorporating separate inhaler combinations [fluticasone, budesonide, beclometasone, or flunisolide plus salmeterol or formoterol]), the pooled incidences of OCS exacerbations were 16.0% (95% CI: 14.2, 17.8%, n/N = 258/1615) and 16.7% (95% CI: 14.9, 18.5, n/N = 275/1643), respectively. CONCLUSIONS: The incidence of exacerbations in two fixed-dose fluticasone/formoterol studies was low and less than in the majority of comparable published studies involving other ICS/LABA combinations. This difference could not be readily explained by differences in features of the respective studies and may be related to the favorable pharmacological/mechanistic characteristics of the constituent components fluticasone and formoterol compared to other drugs in their respective classes.

Fluticasone/formoterol: a new single-aerosol combination therapy for patients with asthma.

International asthma management guidelines recommend a long-acting ß(2)-agonist (LABA) as add-on therapy in patients whose asthma is not controlled by low-dose inhaled corticosteroid (ICS) monotherapy. Treatment with a single inhaler containing an ICS/LABA combination is advocated because it may facilitate adherence to a regimen. When prescribing ICS/LABA combination therapy, the potency of the ICS and the speed of onset of the LABA are considered important factors; therefore, an inhaled therapy containing components with these properties may be valued by physicians. The ICS fluticasone propionate (fluticasone) has potent and sustained anti-inflammatory effects, and the LABA formoterol fumarate (formoterol) provides rapid bronchodilation; the efficacy and safety profiles of these agents have been well established in clinical practice. Fluticasone and formoterol have been combined, for the first time, in a single hydrofluoroalkane-based aerosol (flutiform®; fluticasone propionate/formoterol fumarate). Here, we review data from the published randomized, controlled, clinical trials that demonstrate the efficacy and tolerability of this product. It has been shown that fluticasone/formoterol is more efficacious than fluticasone or formoterol given alone, and provides similar improvements in lung function to fluticasone and formoterol administered concurrently via separate inhalers. Fluticasone/formoterol has similar efficacy and tolerability profiles to budesonide/formoterol and fluticasone/salmeterol, but with the additional benefit of more rapid bronchodilation than fluticasone/salmeterol.

Onset of bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomized study.

INTRODUCTION: The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta(2)-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments. METHODS: Adults with mild-to-moderate-severe persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 µg twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 µg b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV(1)] was ≥12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV(1) were assessed at days 0 (baseline) and 84. RESULTS: Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05-2.05]) and 84 (HR = 1.77 [95% CI 1.14-2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96-8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14-42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57-7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65-4.93]; P = 0.011). CONCLUSION: These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma.

Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain.

UNLABELLED: This randomized, double-blind, placebo- and active-controlled, parallel-group study was designed to demonstrate the superiority of oxycodone in combination with naloxone in a prolonged release (PR) formulation over placebo with respect to analgesic efficacy. The active control group was included for sensitivity and safety analyses, and furthermore to compare the analgesic efficacy and bowel function of oxycodone PR/naloxone PR with oxycodone PR alone. The analgesic efficacy was measured as the time from the initial dose of study medication to multiple pain events (ie, inadequate analgesia) in patients with moderate to severe chronic low back pain. The full analysis population consisted of 463 patients. The times to recurrent pain events were significantly longer in the oxycodone PR/naloxone PR group compared with placebo (P < .0001-.0003); oxycodone PR/naloxone PR reduced the risk of pain events by 42% (P < .0001; full analysis population). The appearance of pain events was comparable for oxycodone PR/naloxone PR versus oxycodone PR, confirming that the addition of naloxone PR to oxycodone PR in a combination tablet did not negatively affect analgesic efficacy of the opioid. Furthermore, oxycodone PR/naloxone PR offers benefits in terms of an improvement in bowel function. In a therapeutic area of great unmet need, therefore, the combination tablet of oxycodone PR/naloxone PR offers patients effective analgesia while improving opioid-induced bowel dysfunction. Taken together with the observation that the safety profile of oxycodone PR/naloxone PR is consistent with that expected from other opioid analgesics except opioid-induced constipation, these findings indicate that the addition of naloxone to oxycodone in a PR combination tablet offers improved tolerability. Oxycodone PR/naloxone PR is therefore a promising new treatment approach for the management of chronic pain. PERSPECTIVE: This study evaluated the analgesic efficacy and safety of the combination of oxycodone PR/naloxone PR in chronic nonmalignant pain. Opioids are often reduced in dosage or even discontinued as a result of impaired bowel function, leading to insufficient pain treatment. Not only does oxycodone PR/naloxone PR demonstrate analgesic efficacy comparable with oxycodone PR, but it also improves opioid-induced bowel dysfunction, and may therefore improve the acceptability of long-term opioid treatment for chronic pain.