CLINICAL REVIEWS Aclidinium bromide
Aclidinium bromide for the treatment of chronic obstructive pulmonary disease Lowell E. Stone, Jessica W. Skelley, Jeffrey A. Kyle, and Lindsey K. Elmore
A
clidinium bromide is a longacting inhaled anticholinergic medication approved for the long-term maintenance of bronchospasm associated with chronic obstructive pulmonary disease (COPD).1 COPD is responsible for 5% of deaths worldwide2 and is a major cause of preventable morbidity and premature death.3 COPD’s trademark symptoms are breathlessness and abnormal sputum production, and the mainstays of treatment are tobacco cessation, bronchodilators, inhaled anticholinergics, and inhaled and systemic corticosteroids.3 Until recently, there was only one long-acting inhaled anticholinergic medication on the market, tiotropium bromide.4 The Food and Drug Administration approved the use of aclidinium bromide (Tudorza Pressair, Forest Pharmaceuticals, St. Louis, MO) on July 23, 2012. Aclidinium bromide has been approved for use internationally in all European Union states as well as Iceland, Norway, Turkey, and the Russian Federation and all other Commonwealth of Independent States members.5 Here, we review the safety, efficacy, phar-
Purpose. The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed. Summary. Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPDassociated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to
macokinetics, pharmacodynamic properties, and clinical application of aclidinium in patients with COPD. Pharmacology Acetylcholine is a common neurotransmitter found in the airways that may cause airway smooth muscle contraction and mucus secretion. Through its action on muscarinic
Lowell E. Stone, Pharm.D., is Postgraduate Year 1 Community Pharmacy Practice Resident; Jessica W. Skelley, Pharm.D., is Assistant Professor of Pharmacy Practice, Department of Pharmacy Practice; Jeffrey A. Kyle, Pharm.D., BCPS, is Associate Professor of Pharmacy Practice, Department of Pharmacy Practice; and Lindsey K. Elmore, Pharm.D., BCPS, is Assistant Professor of Pharmacy Practice, Department of Pharmacy Practice, McWhorter School of Pharmacy, Samford University, Birmingham, AL.
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one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy). Conclusion. Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use. Am J Health-Syst Pharm. 2014; 71:386-93
receptors, acetylcholine may contribute to airway remodeling and the progression of COPD.6 There are five different subtypes of muscarinic receptors, designated M1–M5. Receptors M1–M3 are found in the airways, whereas bronchial and tracheal smooth muscle contraction is primarily due to the action of acetylcholine on M3.6,7 Aclidinium
Address correspondence to Dr. Stone ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0301-0386$06.00. DOI 10.2146/ajhp130077
CLINICAL REVIEWS
bromide is a long-acting antimuscarinic agent with similar affinity for all subtypes of muscarinic cholinergic receptors (M1–M5).1,7 It exhibits its pharmacologic effects, however, through inhibition of the M3 receptor, leading to bronchodilation in the airways.1,7 Aclidinium bromide dissociates more rapidly from the M2 receptor than the M3 receptor, which may be beneficial in patients with COPD since stimulation of the M2 receptor inhibits the release of acetylcholine.6,7 Pharmacokinetics and pharmacodynamics Aclidinium bromide is quickly absorbed, with the maximum concentration (Cmax) generally occurring within five minutes after once- or twice-daily dosing, regardless of the dose studied (200, 400, or 800 mg).8,9 Plasma concentrations of aclidinium bromide then decline rapidly to 0.05), 148 mL with 200 mg (p = 0.006), 128 mL with 400 mg (p = 0.018) Week 12: FEV1 improved by 61 mL vs. placebo (p < 0.001) Week 28: FEV1 improved by 67 mL vs. placebo (p < 0.001) Week 12: FEV1 improved by 63 mL vs. placebo (p < 0.001) Week 28: FEV1 improved by 59 mL vs. placebo (p < 0.001) Treatment difference of 221 mL vs. placebo (p < 0.0001)
a COPD = chronic obstructive pulmonary disease, FEV1 = forced expiratory volume in one second, AUC0–12/12 = area under the curve (numerals denote time period of data collection divided by number of hours over which data were averaged).
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CLINICAL REVIEWS
exacerbation. In ACCLAIM/COPD I, a higher percentage of patients had an improvement in the SGRQ score of at least 4 units at 52 weeks with aclidinium bromide versus placebo use (48.1% versus 39.5%, p = 0.025); although the percentage of patients in ACCLAIM/COPD II who achieved the same degree of SGRQ improvement was also higher relative to placebo users, the difference between groups was not statistically significant (39.0% versus 32.8%, p = 0.074).13 In ACCLAIM/COPD I, the mean improvement from baseline in TDI score was significantly greater with aclidinium bromide versus placebo use (mean change in score, 1.83 units versus 0.61 unit; p < 0.0001), but the between-group difference was not significant in ACCLAIM/COPD II (mean change in TDI score, 1.61 units versus 1.09 units; p = 0.12).13 The time to the first moderate or severe COPD exacerbation was significantly delayed in patients receiving aclidinium bromide versus placebo in ACCLAIM/COPD II (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.55–0.92; p = 0.01) but not in ACCLAIM/COPD I (HR, 1.0; 95% CI, 0.72–1.33; p = 0.9).13 In ACCLAIM/COPD II, statistically significant differences were observed between the aclidinium bromide and placebo groups with regard to cough and sputum production, breathlessness, wheezing, and use of daily rescue medicine (p < 0.05 for all); these improvements were not seen in ACCLAIM/COPD I.13 In both trials, aclidinium bromide appeared to be safe and improved lung function, but the improvements, relative to those seen with placebo use, were smaller than the predetermined minimum clinically important difference (MCID) in trough FEV1 (i.e., >100–120 mL). 13 The MCID for improvements in trough FEV1 was used to determine if the improvements seen with aclidinium bromide versus placebo use were of clinical
importance; however, this value is often based on expert opinion rather than validated measures.13 Due to the potential limitation of once-daily dosing, additional studies investigating increased dosing frequency were also conducted. Twice-daily dosing. In a doubleblind, double-dummy, crossover Phase IIa trial, 30 patients were randomly assigned to receive aclidinium bromide 400 mg twice daily, tiotropium bromide 18 mg once daily, or placebo, with each administered for 15 days and a 9- to 15-day washout period between treatments. Patients included in the study had a diagnosis of COPD, were at least 40 years of age, had an FEV1-toFVC ratio of
Aclidinium bromide for the treatment of chronic obstructive pulmonary disease Lowell E. Stone, Jessica W. Skelley, Jeffrey A. Kyle, and Lindsey K. Elmore
A
clidinium bromide is a longacting inhaled anticholinergic medication approved for the long-term maintenance of bronchospasm associated with chronic obstructive pulmonary disease (COPD).1 COPD is responsible for 5% of deaths worldwide2 and is a major cause of preventable morbidity and premature death.3 COPD’s trademark symptoms are breathlessness and abnormal sputum production, and the mainstays of treatment are tobacco cessation, bronchodilators, inhaled anticholinergics, and inhaled and systemic corticosteroids.3 Until recently, there was only one long-acting inhaled anticholinergic medication on the market, tiotropium bromide.4 The Food and Drug Administration approved the use of aclidinium bromide (Tudorza Pressair, Forest Pharmaceuticals, St. Louis, MO) on July 23, 2012. Aclidinium bromide has been approved for use internationally in all European Union states as well as Iceland, Norway, Turkey, and the Russian Federation and all other Commonwealth of Independent States members.5 Here, we review the safety, efficacy, phar-
Purpose. The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed. Summary. Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPDassociated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to
macokinetics, pharmacodynamic properties, and clinical application of aclidinium in patients with COPD. Pharmacology Acetylcholine is a common neurotransmitter found in the airways that may cause airway smooth muscle contraction and mucus secretion. Through its action on muscarinic
Lowell E. Stone, Pharm.D., is Postgraduate Year 1 Community Pharmacy Practice Resident; Jessica W. Skelley, Pharm.D., is Assistant Professor of Pharmacy Practice, Department of Pharmacy Practice; Jeffrey A. Kyle, Pharm.D., BCPS, is Associate Professor of Pharmacy Practice, Department of Pharmacy Practice; and Lindsey K. Elmore, Pharm.D., BCPS, is Assistant Professor of Pharmacy Practice, Department of Pharmacy Practice, McWhorter School of Pharmacy, Samford University, Birmingham, AL.
386
Am J Health-Syst Pharm—Vol 71 Mar 1, 2014
one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy). Conclusion. Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use. Am J Health-Syst Pharm. 2014; 71:386-93
receptors, acetylcholine may contribute to airway remodeling and the progression of COPD.6 There are five different subtypes of muscarinic receptors, designated M1–M5. Receptors M1–M3 are found in the airways, whereas bronchial and tracheal smooth muscle contraction is primarily due to the action of acetylcholine on M3.6,7 Aclidinium
Address correspondence to Dr. Stone ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0301-0386$06.00. DOI 10.2146/ajhp130077
CLINICAL REVIEWS
bromide is a long-acting antimuscarinic agent with similar affinity for all subtypes of muscarinic cholinergic receptors (M1–M5).1,7 It exhibits its pharmacologic effects, however, through inhibition of the M3 receptor, leading to bronchodilation in the airways.1,7 Aclidinium bromide dissociates more rapidly from the M2 receptor than the M3 receptor, which may be beneficial in patients with COPD since stimulation of the M2 receptor inhibits the release of acetylcholine.6,7 Pharmacokinetics and pharmacodynamics Aclidinium bromide is quickly absorbed, with the maximum concentration (Cmax) generally occurring within five minutes after once- or twice-daily dosing, regardless of the dose studied (200, 400, or 800 mg).8,9 Plasma concentrations of aclidinium bromide then decline rapidly to 0.05), 148 mL with 200 mg (p = 0.006), 128 mL with 400 mg (p = 0.018) Week 12: FEV1 improved by 61 mL vs. placebo (p < 0.001) Week 28: FEV1 improved by 67 mL vs. placebo (p < 0.001) Week 12: FEV1 improved by 63 mL vs. placebo (p < 0.001) Week 28: FEV1 improved by 59 mL vs. placebo (p < 0.001) Treatment difference of 221 mL vs. placebo (p < 0.0001)
a COPD = chronic obstructive pulmonary disease, FEV1 = forced expiratory volume in one second, AUC0–12/12 = area under the curve (numerals denote time period of data collection divided by number of hours over which data were averaged).
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CLINICAL REVIEWS
exacerbation. In ACCLAIM/COPD I, a higher percentage of patients had an improvement in the SGRQ score of at least 4 units at 52 weeks with aclidinium bromide versus placebo use (48.1% versus 39.5%, p = 0.025); although the percentage of patients in ACCLAIM/COPD II who achieved the same degree of SGRQ improvement was also higher relative to placebo users, the difference between groups was not statistically significant (39.0% versus 32.8%, p = 0.074).13 In ACCLAIM/COPD I, the mean improvement from baseline in TDI score was significantly greater with aclidinium bromide versus placebo use (mean change in score, 1.83 units versus 0.61 unit; p < 0.0001), but the between-group difference was not significant in ACCLAIM/COPD II (mean change in TDI score, 1.61 units versus 1.09 units; p = 0.12).13 The time to the first moderate or severe COPD exacerbation was significantly delayed in patients receiving aclidinium bromide versus placebo in ACCLAIM/COPD II (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.55–0.92; p = 0.01) but not in ACCLAIM/COPD I (HR, 1.0; 95% CI, 0.72–1.33; p = 0.9).13 In ACCLAIM/COPD II, statistically significant differences were observed between the aclidinium bromide and placebo groups with regard to cough and sputum production, breathlessness, wheezing, and use of daily rescue medicine (p < 0.05 for all); these improvements were not seen in ACCLAIM/COPD I.13 In both trials, aclidinium bromide appeared to be safe and improved lung function, but the improvements, relative to those seen with placebo use, were smaller than the predetermined minimum clinically important difference (MCID) in trough FEV1 (i.e., >100–120 mL). 13 The MCID for improvements in trough FEV1 was used to determine if the improvements seen with aclidinium bromide versus placebo use were of clinical
importance; however, this value is often based on expert opinion rather than validated measures.13 Due to the potential limitation of once-daily dosing, additional studies investigating increased dosing frequency were also conducted. Twice-daily dosing. In a doubleblind, double-dummy, crossover Phase IIa trial, 30 patients were randomly assigned to receive aclidinium bromide 400 mg twice daily, tiotropium bromide 18 mg once daily, or placebo, with each administered for 15 days and a 9- to 15-day washout period between treatments. Patients included in the study had a diagnosis of COPD, were at least 40 years of age, had an FEV1-toFVC ratio of
