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COPD 2013: An update on treatment and newly approved for pharmacists Katie Campoli Meyer

Katie Campoli Meyer, PharmD, is Clinical Abstract Pharmacist, Lourdes Specialty Hospital of Southern New Jersey, Willingboro.

Objective: To educate pharmacists about the Global Strategy for the Diagnosis, Correspondence: Katie Meyer, PharmD, Lourdes Specialty Hospital of Southern New Management, and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) Jersey, 218 A Sunset Rd., Willingboro, NJ guidelines for treatment of chronic obstructive pulmonary disease (COPD), newly 08046. E-mail: [email protected] approved medications, and recent developments since the guidelines were pub- Reviewer: Dennis Williams, PharmD, BCPS, lished. AE-C, Associate Professor, School of Phar- Summary: The evidence-based GOLD guidelines provide recommendations macy, University of North Carolina, Chapel Hill for clinicians managing patients with COPD. These guidelines were revised most Published concurrently in Pharmacy Today recently in 2013. Three new medications ( maleate, , and the Journal of the American Pharma- cists Association (available online at www. and furoate/) have been approved in the previous 2 years. japha.org). Adding to the armamentarium of medications for treating COPD is useful. Studies also have been conducted to determine which inhaled agents are preferred for use when long-acting are needed as mono- and combination therapy. In addition, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and macrolides are being studied for use in COPD. An extensive COPD pipeline con- sists of many oral and inhaled medications, including and glycopyrro- nium maleate, which are in Phase III clinical trials. adherence is a very important piece of COPD management. Pharmacists play an integral role in drug selection and patient education to ensure the best possible outcomes. Conclusion: The GOLD guidelines represent the standard of care for COPD management. New drug approvals and recent research may affect practitioner Learning objectives choices in managing the disease. Pharmacists can improve medication adherence ■■ Discuss appropriate medication man- and selection in order to maximize therapeutic effectiveness and ensure that pa- agement of stable chronic obstructive pulmonary disease (COPD) based on tients are using inhalation delivery devices optimally. the 2013 revised Global Strategy for the Keywords: Chronic obstructive pulmonary disease, GOLD guidelines, inda- Diagnosis, Management, and Preven- caterol maleate, aclidinium bromide, fluticasone furoate/vilanterol, adherence tion of Chronic Obstructive Pulmonary (medication). Disease guidelines. Pharmacy Today. 2013(Nov);19(11):53–64. ■■ Describe the mechanism of action, rec- ommended dose, major adverse effects, drug interactions, contraindications, and place in therapy for indacaterol Accreditation information maleate, aclidinium bromide, and fluti- Provider: American Pharmacists Association ACPE number: 0202-0000-13-225-H01-P casone furoate/vilanterol. Target audience: Pharmacists CPE credit: 2 hours (0.2 CEUs) ■■ Compare olodaterol and glycopyrro- Release date: November 1, 2013 Fee: There is no fee associated with this activity nium maleate, which are medications in Expiration date: November 1, 2016 for members of the American Pharmacists As- the COPD pipeline. Learning level: 2 sociation. There is a $15 fee for nonmembers. ■■ Discuss recent developments in the treatment of COPD, including choice among inhaled agents, 3-hydroxy- The American Pharmacists Association is accredited by the Accreditation Council 3-methylglutaryl-coenzyme A for Pharmacy Education as a provider of continuing pharmacy education (CPE). The reductase reductase inhibitors, and ACPE Universal Activity Number assigned to this activity by the accredited provider is macrolides. 0202-0000-13-225-H01-P. ■■ Recognize the importance of medica- Disclosure: Dr. Williams declares that his spouse/partner is an employee and a stock/sharehold- tion adherence, barriers to adherence, er of GlaxoSmithKline. Dr. Meyer and APhA’s education staff declare no conflicts of interest or and the pharmacist’s role in improving financial interests in any product or service mentioned in this activity, including grants, employ- patient adherence to COPD treatment ment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see the APhA regimens. Accreditation Information section at www.pharmacist.com/education.

www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 53 CPE copd update

Case study tients who present with these symptoms plus have a history Chief complaint. J.P. is a 72-year-old man who presents to his physi- of exposure to irritants (e.g., tobacco smoke, occupational cian’s office with worsening symptoms of shortness of breath and chemicals) or a family history of COPD. Postbronchodila- decreased oxygen saturation of 80%. The patient was placed in a bed, tor spirometry confirms a suspected diagnosis if the pa- put on oxygen via nasal cannula, and given a treatment and tient’s forced expiratory volume in 1 second (FEV ) divided an intravenous steroid injection. The patient’s oxygen saturation (O ) 1 2 2 improved to 96% posttreatment. by forced vital capacity (FVC) is less than 70%. The Global History of current illness. The patient has a past medical history Strategy for the Diagnosis, Management, and Prevention of noteworthy for chronic obstructive pulmonary disease (COPD) second- Chronic Obstructive Pulmonary Disease (GOLD) guidelines ary to a long-term smoking history. The patient quit smoking 5 years classify COPD severity in patients into four grades upon ago when he was diagnosed with COPD. He has had to use his albuterol diagnosis (Table 1). Patients are further classified into four inhaler much more frequently during the previous 3 days (at least four groups that incorporate patient-specific symptoms based to five times per day). He was given a steroid taper about a month ago for a COPD exacerbation. He also has , dyslipidemia, on exacerbation rate and validated questionnaires regard- overactive bladder, and insulin-dependent diabetes. ing symptom severity and frequency (Table 2). The patient Allergies. The patient is allergic to clarithromycin (rash). group classification aides in determining a preferred treat- Current home medications. Insulin glargine 50 units s.c. twice ment regimen. daily, 50 mg orally daily, aspirin 81 mg orally daily, rosuvas- tatin 10 mg orally daily, lisinopril 5 mg orally daily, 12 µg 1. Based on J.P.’s history, in which GOLD group would he be clas- one inhalation twice daily, furosemide 40 mg orally daily, solifenacin sified? 10 mg orally daily, and albuterol 90 µg one inhalation every 4 hours as a. A needed for wheezing. b. B Social history. The patient lives at home with his wife. He has a c. C smoking history of 50 pack-years but stopped smoking 5 years ago. d. D J.P. also worked in a steel mill. He has no history of alcohol or any other recreational drugs. Treatment of stable COPD Vital signs. Blood pressure 171/74 mm Hg, heart rate 109 bpm, The goals of pharmacologic treatment are to reduce symp- respiratory rate 30 breaths per minute, O saturation 80% recovered 2 toms, reduce the frequency and severity of exacerbations, to 96%, temperature 98.6°F, and forced expiratory volume in 1 second and improve exercise tolerance and health status.2 All pa- (FEV ) 40%. 1 tients who smoke should be provided help quitting in order to improve the natural history of COPD. Smoking cessation Chronic obstructive pulmonary disease (COPD) affects programs with replacement therapy and/or phar- an estimated 14.8 million individuals worldwide, with an macologic therapy should be initiated as soon as possible in estimated 12 million cases currently undiagnosed.1 COPD is order to delay the progression of COPD.2 All patients with a leading cause of morbidity and mortality worldwide, re- COPD also should be offered the pneumococcal polysaccha- sulting in an increasing social and economic burden.2 It is ride vaccine. An annual influenza vaccine is indicated for all the third leading cause of death in the United States.3 COPD patients, independent of age, to reduce their risk of complica- costs an estimated $29.5 billion directly and $20.4 billion in tions from infection.2,6 indirect costs annually.2 COPD is most prevalent in men, The GOLD guidelines for pharmacological management smokers, and individuals older than 40 years.4 recommend a stepwise approach to treatment based on pa- COPD is characterized by progressive inflammation that tient classification. All patients should be prescribed a res- causes modification and narrowing of pulmonary airways, cue inhaler (short-acting beta agonist or beta agonist/anti- leading to development of chronic airflow limitation. Dam- cholinergic combination). Treatment of patients in group A age to the parenchyma of the lungs also occurs. Chronic consists of a short-acting used only as needed inflammation causes changes in small airways and lung for symptomatic relief. These patients have few symptoms parenchyma that lead to decreased lung recoil and an in- and a low exacerbation risk. Long-acting bronchodilators are ability of the airways to remain open during expiration.2 recommended as the agent of choice for patients in group The inflammatory process is initiated by macrophages and epithelial cells in response to noxious stimuli such as ciga- Table 1. Classification of severity of airflow limitation in COPD (based on rette smoke or environmental toxins. Following repeated postbronchodilator FEV1) exposure, a variety of chemicals including but not limited GOLD 1 Mild FEV1 ≥80% predicted to tumor necrosis factor (TNF), interleukin 8, and leukotri- GOLD 2 Moderate 50% ≤FEV <80% predicted ene B4 are activated. These cytokines and chemoattractants 1 GOLD 3 Severe 30% ≤FEV <50% predicted bring more inflammatory cells into the lungs, which release 1 GOLD 4 Very severe FEV <30% predicted a variety of chemicals that cause irreversible damage to the 1 5 Abbreviations used: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory lung tissues. volume in 1 second; FVC, forced vital capacity; GOLD, Global Strategy for the Diagnosis, Symptoms of COPD include progressive dyspnea that Management, and Prevention of Chronic Obstructive Pulmonary Disease. All patients FEV /FVC <70%.2 is persistent and worsens with exercise, chronic cough, and 1 Reprinted with permission from the Global Initiative for Chronic . sputum production. Diagnosis of COPD is considered in pa-

54 PharmacyToday • NOVEMBER 2013 www.pharmacytoday.org CPE copd update

Table 2. Summary of GOLD COPD assessment2 Group A Group B Group C Group D GOLD 1 or GOLD 2 GOLD 1 or GOLD 2 GOLD 3 or GOLD 4 GOLD 3 or GOLD 4 0–1 exacerbation/year 0-1 exacerbation/year ≥2 exacerbations/year ≥2 exacerbations/year Low level of symptoms High level of symptoms Low level of symptoms High level of symptoms Abbreviations used: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Strategy for the Diagnosis, Manage- ment, and Prevention of Chronic Obstructive Pulmonary Disease.

Table 3. Summary of beta-2 agonists used in the treatment of COPD2,20 Drug Formulations Dosage Duration of action (h) Short acting Levalbuterol MDI, neb 0.63–1.25 mg every 4–6 h as needed 6–8 Albuterol MDI, neb 2.5 mg every 4–6 h as needed 4–6 MDI 400 µg every 4–6 h as needed 4–6 Long acting Neb 15 µg every 12 h 12 Formoterol DPI, neb 12–20 µg every 12 h 12 DPI 50 µg every 12 h 12 Indacaterola DPI 75 µg daily 24 Abbreviations used: DPI, dry powder inhaler; MDI, metered-dose inhaler; neb, nebulizer solution. aIndacaterol discussed in further detail. B. These patients have increased symptoms and can benefit 18 µg daily and has a 24-hour duration of action. Tiotropium from continuous therapy. Group C patients should be treated may be challenging to use for patients who have difficulty with both an inhaled and bronchodilator be- with dexterity as it requires them to take a capsule out of a cause of their high exacerbation rate. Last, group D patients packet and load the device before inhaling.7 Aclidinium bro- also should be started on combination therapy, but if it fails, mide is the newest and will be discussed in a third drug can be added to improve symptoms.2 Individu- further detail later. alizing agent choice based on patient-specific factors is im- portant. Research currently is being done to evaluate which Beta-2 agonists drug class is superior and whether adding medications cur- Beta-2 agonists relax bronchial smooth muscles by stimulat- rently marketed for indications other than COPD can help ing beta-2– receptors. Common adverse effects decrease the exacerbation rate. associated with this class include tremor, , and cardiac rhythm disturbance.2 Patients should be educated not Bronchodilators to exceed their prescribed dose, as the majority of adverse ef- Bronchodilators increase airflow by altering smooth muscle fects occur with overuse. The most common drug classes that tone. Those indicated for treatment include interact with beta-2 agonists include , steroids, tricy- and beta-2 agonists. clic (TCAs), monoamine oxidase inhibitors (MAOIs), and systemic beta blockers. A recently published Anticholinergics study of 76,661 patients with COPD found a significant in- Anticholinergics bind to muscarinic receptors and block the crease in the rate of severe cardiac dysrhythmias with new action of acetylcholine, which reduces bronchomotor tone use of short-acting beta-2 agonists. The retrospective study leading to bronchodilation. They are generally a safe drug did not assess patient-specific factors such as underlying class when inhaled, with dry mouth being the most com- cardiac disease and duration of use of the beta agonist; thus, mon adverse effect.2 Systemic anticholinergics being used further research is warranted.8 Mortality risk increases when for different indications, such as oxybutynin, should be used beta-2 agonists are used alone for the treatment of , with caution because of the increased potential for anticho- but this association has not been found in COPD.2,9,10 Com- linergic adverse effects. Three inhaled anticholinergic agents mercially available beta-2 agonists are summarized in Table 3. are commercially available. is a short- acting anticholinergic agent available in both a metered in- haler and nebulized solution. A typical nebulized dose is 0.5 Inhaled corticosteroids exert anti-inflammatory effects by mg inhaled every 6 to 8 hours, consistent with its duration of binding to receptors. Corticosteroids improve action.2 is a long-acting anticholinergic symptoms and reduce the frequency of exacerbations in that is available in a dry powder inhaler. Tiotropium is dosed COPD but do not modify the occurrence of long-term decline www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 55 CPE copd update

Table 4. Summary of inhaled corticosteroids used in treatment of COPD2 with a history of exacerbations. is an oral medication dosed at 500 µg by mouth daily. Because it is Drug Formulations Dosage absorbed systemically, roflumilast has an extensive adverse Single agent effect profile compared with inhaled agents. The most Beclomethasone MDI Max 640 µg/day divided b.i.d. common adverse effects associated with use include nausea, DPI, neb Max: 1,440 µg/day divided b.i.d. abdominal pain, , sleep disturbances, reduced MDI Max 320 µg/day divided b.i.d. appetite, and headache. These adverse effects may lessen Fluticasone MDI, DPI Max 1,000 µg/day divided b.i.d. over time with continued treatment. Roflumilast should DPI Max 440 µg/day divided once be used in caution in patients with depression because of daily to b.i.d. an increased frequency of anxiety, depression, and sleep Combination agent disorders when using the drug. Patients who are taking roflumilast should have their weight monitored regularly, as Budesonide/ Max 640 µg/18 µg/day divided 2,12 formoterol MDI b.i.d. it has been implicated in causing substantial weight loss. Ongoing long-term studies will further evaluate safety and Mometasone/ Max 800 µg/20 µg/day divided 13 formoterol MDI b.i.d. the risk versus benefit of use. Because of safety concerns and limited clinically significant efficacy data, roflumilast Fluticasone/ Max 1,000 µg/100 µg/day di- salmeterol DPI vided b.i.d. should be reserved for patients who have severe COPD with Fluticasone/ chronic bronchitis that is inadequately controlled by inhaled 2,14 vilanterola DPI Once-daily dosing bronchodilators. Other phosphodiesterase inhibitors cur- Abbreviations used: DPI, dry powder inhaler; MDI, metered-dose inhaler; neb, nebulizer rently in the pipeline include an inhaled version in Phase II solution. trials.14 aFluticasone/vilanterol discussed in further detail. is a derivative. The exact mecha- in pulmonary function or the rate of mortality.11 When used nism of action of this class is unknown. Animal studies sug- in combination with beta-2 agonists, inhaled corticosteroids gest that it exhibits similar properties to a phosphodiesterase are more effective in reducing exacerbations and improving inhibitor. A limited amount of data support use of theophyl- lung function compared with corticosteroids alone.2,11 line in COPD. The current data only support use of the slow- The adverse effects commonly associated with cortico- release preparations. The of theophylline steroids include oral candidiasis, hoarse voice, skin bruising, vary widely among patients. Certain diseases, including he- pneumonia, and decreased bone mineral density. All of the patic disease, severe COPD, , and cigarette smok- inhaled corticosteroids are cytochrome P450 (CYP)3A4 sub- ing, require factor adjustment when estimating a patient’s strates; therefore, caution is advised when adding medica- clearance. Theophylline is metabolized via the CYP system, tions that will induce or inhibit this class. Patients with high and therefore it has a wide array of drug interactions. Cimeti- exacerbation risk and severe symptoms benefit from cortico- dine, ciprofloxacin, diltiazem, , , steroid addition.2 Several formulations of corticosteroids are and verapamil are just a few of the medications that require commercially available, both alone and in combination with close monitoring and factor adjustment when considering beta-2 agonists (Table 4). theophylline dose. It also has many adverse effects, includ- ing headaches, insomnia, nausea, heartburn, and more seri- 2. Which of J.P.’s medications interact with his formoterol? ous adverse effects, such as grand mal convulsions and fatal a. Lisinopril atrial and ventricular dysrhythmias. Because of its within- b. Aspirin c. Atenolol subject variation in metabolism, treatment recommenda- d. Solifenacin tions include measuring serum theophylline concentrations at least every 24 hours in acutely ill patients and at 6- to 3. Which medication should be used with caution in J.P. based on 12-month intervals in patients receiving long-term therapy. his history? The target therapeutic concentration is 5 to 15 mg/L.15 The- a. Tiotropium 18 µg inhaled daily ophylline is not recommended for use in COPD unless other b. Bedesonide/fomoterol 80/4.5 µg inhaled b.i.d. bronchodilators are unavailable or unaffordable.2 c. Albuterol 90 µg inhaled every 4 to 6 hours as needed d. Salmeterol 50 g inhaled every 12 hours µ Treatment of COPD exacerbations Other agents A COPD exacerbation is defined as a patient presenting Two additional drugs are alternatives for use in COPD when with an acute change of symptoms deviating from their it is not adequately controlled with standard therapy or when daily norm that leads to a change in medication.2,16 Several appropriate based on patient-specific factors. Roflumilast factors can precipitate a COPD exacerbation, including bac- is a phosphodiesterase-4 inhibitor that exerts its action by terial or viral infections, air pollution, and other unknown increasing intracellular cyclic adenosine monophosphate, causes. Treatment goals are to improve the current exacerba- leading to reduced inflammation. It is indicated specifically tion and prevent recurrent exacerbations. Short-acting beta-2 in patients with chronic bronchitis who have severe COPD agonists are the bronchodilator of choice during an exacer-

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bation. Short-acting anticholinergics may be added as well. it may be an appropriate option in patients who have diffi- Use of short-course systemic corticosteroids, such as pred- culties using tiotropium because of its delivery mechanism. nisolone for 10 to 14 days, also has been shown to improve Compared with tiotropium, a disadvantage of aclidinium is lung function and reduce recovery time.2 Antibiotics should that it must be used twice daily, which may lead to decreased be reserved for patients who show clinical signs of bacterial regimen adherence. Although trials have been completed, no infection (e.g., increased dyspnea, sputum volume, sputum studies have been published regarding use of aclidinium in purulence), unless the patient requires mechanical ventila- combination with formoterol.19 tion. Studies have shown that a mortality benefit may exist in 2,17 5. Which of J.P.’s medications might interact with aclidinium? ventilated patients. a. Atenolol 4. What nebulizer treatment is indicated for treatment of J.P.’s b. Insulin glargine acute exacerbation? c. Solifenacin a. Bedesonide 0.5 mg via nebulizer d. Formoterol b. Albuterol 2.5 mg via nebulizer c. Formoterol 20 µg via nebulizer Indacaterol maleate d. Acetylcysteine 400 mg via nebulizer Indacaterol is a long-acting beta-2 agonist indicated for long- term maintenance bronchodilator treatment of patients Newly approved drugs for managing COPD with COPD. Indacaterol’s main advantage compared with Aclidinium bromide other drugs in its class is its convenient once-daily dosage Aclidinium is a long-acting anticholinergic that was ap- regimen. Indacaterol is available in a 75-µg hard capsule that proved for use in July 2012. It is indicated for the long-term must be removed from a blister packet and loaded into a dry maintenance treatment of COPD. The drug is available in a powder inhaler before inspiration. The recommended dose multidose dry powder inhaler that does not require loading of indacaterol is 75 µg inhaled once daily, at the same time a capsule. This may offer an advantage over tiotropium for each day. 20 selected patients. Aclidinium’s recommended dosage is 400 The effectiveness of indacaterol was demonstrated in sev- µg (one puff) inhaled twice daily. eral placebo controlled studies that analyzed patients with

The effectiveness of aclidinium for COPD patients was an FEV1 of at least 30% but less than 80% predicted normal demonstrated in three placebo-controlled studies in patients and FEV1/FVC less than 70%. The primary endpoint was an with an FEV1 of at least 30% and less than 80% predicted and improvement of bronchodilation, as assessed by an improve-

FEV1/FVC less than 70%. The studies primary endpoint was ment of FEV1 after 12 weeks of treatment. Indacaterol also an improvement in bronchodilation as measured by an in- was compared with tiotropium, but only at doses of 150 to crease in FEV1 at 12 weeks compared with placebo. All three 600 µg per day. At increased dosage, indacaterol was at least studies resulted in statistically significantly greater broncho- as effective as tiotropium and appeared to be more effective dilation at 12 weeks.18 Data comparing aclidinium and tiotro- than formoterol and salmeterol; however these studies were pium are limited. not conducted with the FDA-approved 75-µg dose. The high- The adverse reactions most commonly implicated with er dosages also were implicated with increased frequency of aclidinium include headache, cough, and nasopharyngi- cardiovascular and cerebrovascular adverse events.21–23 tis. Possibility of immediate hypersensitivity reaction is an The most common adverse reactions associated with in- important, uncommon adverse reaction. Aclidinium has a dacaterol are cough, oropharyngeal pain, nasopharyngitis, similar chemical structure to that of atropine; thus, caution headache, and nausea. Immediate hypersensitivity reactions, is advised in patients with a history of hypersensitivity. Acli- hypokalemia, and hyperglycemia also are of concern. Like dinium also should be used in caution in patients with se- other beta-2 agonists, indacaterol can cause increases in heart vere hypersensitivity to milk proteins. Aclidinium should be rate or blood pressure and prolong the QT interval; therefore, discontinued if hypersensitivity reactions occur, and alter- it should be used in caution in patients with cardiovascular native therapies should be considered. Aclidinium also may disease (CVD).20 worsen narrow-angle glaucoma, so caution should be used Indacaterol should not be used in acutely deteriorating in this population. COPD or for relief of acute symptoms. Indacaterol should be Information regarding drug interactions with aclidinium used in caution in patients with convulsive disorders, thy- is limited to the potential for interaction with anticholinergic rotoxicosis, or those who are sensitive to sympathomimetic medications used concomitantly. Aclidinium is not metabo- drugs. Indacaterol is Category C and therefore lized via the CYP metabolic pathway. Only 0.1% of an acli- should be used in pregnant women only when the benefit dinium dose is excreted in the , making it a potentially outweighs the potential risk to the fetus.20 safe option in patients with renal insufficiency. No dosage Drug interactions with indacaterol include concomi- adjustment is needed in this population.18 tant use with other adrenergic drugs that may potentiate its Aclidinium is the second long-acting anticholinergic sympathomimetic effect. Xanthine derivatives, steroids, or approved for use in COPD in the United States. Although non–potassium-sparing diuretics may increase the chances it does not have the extensive data support of tiotropium, of hypokalemia and electrocardiogram changes. MAOIs, www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 57 CPE copd update

TCAs, and drugs that prolong the QT interval may increase Clinical trials showed a statistically significant decrease indacaterol’s effect on the cardiovascular system. Finally, in exacerbation rate when fluticasone/vilanterol was com- 20 beta blockers may decrease the effectiveness of indacaterol. pared with vilanterol alone in 7,700 patients with an FEV1 less Indacaterol is the first long-acting beta-2 agonist ap- than 70% and at least one documented COPD exacerbation proved for once-daily use. Because clinical trials only have in the year before study enrollment. Nasopharyngitis was compared higher dosages of indacaterol with active compar- the most frequently reported adverse effect in clinical trials. ators, whether it is equally effective in improving lung func- Studies also showed an increased fracture risk (2.2%) and tion or preventing COPD exacerbations at the FDA-approved increased chance of pneumonia (3%) when the combination dose is unclear. The operation of the inhaler for administra- product was compared with vilanterol alone.28 tion also may be difficult in patients who have decreased Fluticasone/vilanterol will be available for distribution dexterity. The use of indacaterol should be reserved for pa- in the third quarter of 2013, according to GlaxoSmithKline. tients who have difficulties with adherence and would ben- It will be the only inhaled corticosteroid/beta agonist com- efit from a once-daily long-acting beta-2 agonist. A trial com- bination dosed once daily. This new medication will most paring indacaterol plus tiotropium versus tiotropium alone likely be used in patients with group C or D COPD who evaluated 2,276 patients with moderate to severe COPD in have difficulty with adherence or prefer a once-daily treat- a double-blind, 12-week study looking at the area under the ment option. Larger-scale studies with vilanterol alone and curve of FEV1 from 5 minutes to 8 hours postdose at week in combination with tiotropium may be warranted and allow

12. A statistically significant improvement in FEV1 was found for greater use of the drug within the COPD population. with the addition of indacaterol to tiotropium; however, the study did not assess risk of COPD exacerbation.24 Further ro- 6. If J.P. needs addition of a long-acting beta-2 agonist, which medication is indicated? bust studies are needed to determine the clinical use of inda- a. Ciclesonide caterol plus tiotropium. b. Beclomethasone dipropionate c. Levalbuterol Newly approved device d. Indacaterol In October 2011, Boehringer Ingelheim gained approval for their first in class Respimat Soft Mist Inhaler. This multiple- 7. If J.P. has difficulty with adherence, which treatment may be a dose device is a propellant-free inhaler that uses liquid for- better option for him? a. Levalbuterol mulations of drug similar to those in . The device b. Indacaterol uses the energy of a compressed spring to generate aerosol at c. Fluticasone furoate/vilanterol a slower rate than that of an MDI, resulting in increased lung d. Theophylline deposition in COPD patients with poor inhaler technique.25 The device was approved for administration of ipratropium/ COPD pipeline albuterol under the brand name Combivent Respimat and An extensive pipeline of chemical entities is currently being became available in mid-2012. Studies also have shown non- investigated for use in COPD. Agents are being developed inferiority when comparing tiotropium delivered via the to target specific receptors of cytokines involved in the in- Respimat device with its currently approved HandiHaler.26 flammatory process associated with COPD with the goal of Patients taking Combivent Respimat should be educated reversing the course itself. Olodaterol, glycopyrronium, and on the proper technique for assembly of the device. A drug umeclidinium/vilanterol are nearing FDA approval. cartridge must be inserted into the device, and after this is done, the inhaler should be given an expiration date of Olodaterol 3 months. The inhaler also needs to be primed before first In January 2013, an FDA advisory committee recommend- use, which may be difficult for some patients to understand. ed approval of Boehringer Ingelheim’s olodaterol based on Community pharmacists should ensure that patients under- Phase III trials. Olodaterol is a long-acting beta-2 agonist stand the proper process for priming before dispensing the administered via the Respimat device. Based on 10 Phase Combivent Respimat inhaler.27 III studies, the advisory committee recommended approval of a dose of 5 µg inhaled once daily gain. Nasopharyngitis, Fluticasone furoate/vilanterol , rash, and arthralgia were the adverse effects most Fluticasone furoate/vilanterol is a combination product that commonly associated with treatment. Patients were not ex- gained approval in May 2013 for long-term maintenance of cluded from trials if they had a history of CVD, and no det- airflow obstruction and reduction of exacerbations in COPD. rimental effects were observed in this population.29 Clinical The product combines the already-marketed inhaled cor- trials comparing olodaterol in combination with tiotropium ticosteroid fluticasone with a newly approved long-acting to olodaterol alone are currently ongoing.30 Information has beta-2 agonist, vilanterol. The product is delivered in a newly not been released regarding olodaterol’s approval or release. patented dry powder inhaler device that when inhaled once daily, delivers 100 µg fluticasone and 25µ g vilanterol.

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Glycopyrronium bromide endpoint was time to the first COPD exacerbation. Patients In October 2012, Novartis gained approval in Europe for gly- included in the study were at least 40 years of age, had a copyrronium bromide, a long-acting smoking history of 10 pack-years or more, had a diagnosis of for treating moderate to severe COPD. The manufacturer COPD with a FEV1 after bronchodilation of 70% or more pre- plans to seek approval in the United States for both mono- dicted, and had at least one documented exacerbation within and combination therapy with indacaterol. Glycopyrronium the previous year. Time to the first COPD exacerbation was is another long-acting anticholinergic agent and is compara- 187 days versus 145 days with salmeterol (P < 0.001). Tiotro- ble with tiotropium. A series of in pium also reduced the annual number of moderate to severe Chronic Obstructive Pulmonary Disease Airways (GLOW) exacerbations (0.64 vs. 0.72, P = 0.002), and fewer deaths oc- studies have assessed glycopyrronium versus placebo and curred in the tiotropium group (1.7%) than in the salmeterol tiotropium.31,32 The GLOW 2 study assessed improvement group (2.1%). The incidence of adverse effects was similar in 36 in FEV1 at 52 weeks and found a statistically significant im- the two groups. provement compared with placebo but not with tiotropium.32 A retrospective, population-based, cohort study was con- The dose most commonly tested in clinical trials is 50 ducted in Ontario, Canada, and included patients 66 years µg inhaled once daily, though studies are being conducted or older who were diagnosed with COPD and were newly with 100 and 200 µg doses. Similar to currently approved prescribed a long-acting inhaled anticholinergic or beta-2 anticholinergic agents, glycopyrronium appears to be agonist. Patients were followed for up to 5.5 years, and the well tolerated. Studies of glycopyrronium alone and in primary endpoint was all-cause mortality. A total of 46,403 combination with indacaterol versus placebo and active patients were evaluated, and mortality was higher in those comparators are ongoing.33 initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled beta-agonist. Umeclidinium/vilanterol Hospitalization rates also were higher in the anticholinergic In September 2013, the Pulmonary-Allergy Drugs Advisory group.37 Of note, the study was not a prospective, random- Committee to FDA recommended approval of GlaxoSmith- ized, controlled trial. Kline’s umeclidinium/vilanterol for long-term, once-daily Data are conflicting regarding which class is superior for maintenance treatment of airflow obstruction in patients initial treatment of COPD when a long-acting agent is need- with COPD based on Phase III trials.34 Umeclidinium/ ed. It is important to keep in mind patient comorbidities that vilanterol is a combination of a newly developed long-acting exist when selecting an agent. For example, in patients with muscarinic antagonist and an already-marketed long-act- history of heart failure, tiotropium would be preferred be- ing beta-2 agonist. The advisory committee recommended cause beta-2 agonists can oppose the benefits of beta blockers that the 62.5/25 µg inhaled once-daily dose gain approval. and worsen cardiac outcomes.38 In patients with renal insuf- Adverse effects most frequently reported in clinical studies ficiency, beta-2 agonists would be preferred, whereas tiotro- were headache, nasopharyngitis, cough, upper respiratory pium could result in increased anticholinergic effects.39 tract infection, and back pain. Because of an imbalance in the number of nonfatal myocardial infarctions compared with placebo in some studies, the panel recommended conducting 8. What action(s) should be taken to reduce J.P.’s exacerbation postmarket studies to further analyze safety.35 Umeclidini- risk? um/vilanterol has potential to be a useful modality in treat- a. Add theophylline 100 mg orally b.i.d. b. Change formoterol to budesonide/formoterol 160 µg/4.5 µg ing moderate to severe COPD because of its once-daily dos- two puffs inhaled b.i.d. ing regimen. It also is the first combination of a long-acting c. Change atenolol to 5 mg orally daily antimuscarinic and beta-2 agonist, which are commonly d. Both b and c are correct. used together in various stages of COPD treatment. 9. Which adverse effect may occur with the addition of the above Recent developments in COPD medication? Tiotropium compared with long-acting a. Pneumonia b. Reduced appetite beta-2 agonists c. Headache The current guidelines for patients classified in GOLD group d. Seizures B (i.e., those with persistent symptoms of COPD who need more than an as-needed bronchodilator) recommend use of Beta-2 agonist/steroid combination selection a long-acting inhaled bronchodilator. The choice between an A recent large-scale, retrospective, observational study in anticholinergic and long-acting beta-2 agonist is currently 5,468 patients with moderate to severe COPD compared based on clinician and patient experience and preferences. budesonide/formoterol with fluticasone/salmeterol for up A 1-year, randomized, double-blind study compared to 11 years. The study compared the ability of the two dif- tiotropium 18 µg daily with salmeterol 50 µg twice daily in ferent combinations to prevent COPD exacerbations. Patients 7,376 patients with moderate to severe COPD. The study was who were included were matched into pairs based on similar funded by the manufacturers of tiotropium. The primary baseline characteristics. Exacerbation rates were found to be www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 59 CPE copd update

0.8 and 1.09 per patient-year in the budesonide/formoterol and fluticasone/salmeterol treatment groups, respectively. 10. If J.P.’s physician would like to add an oral agent to reduce his COPD exacerbation rate, which medication would you recom- These rates corresponded to a 26.6% lower exacerbation rate mend? in the budesonide/formoterol group (P < 0.0001) and a num- a. Theophylline extended release 300 mg orally each morning ber needed to treat with budesonide/formoterol to prevent b. Roflumilast 500 µg orally daily one exacerbation per year of 3.4. The study also reported c. Azithromycin 250 mg orally daily that the yearly rate of COPD-related hospitalizations also d. 40 mg orally daily was significantly lower in the budesonide/formoterol group (29.1% reduction, P < 0.0001). The number needed to treat to Macrolides in COPD prevent one hospitalization per patient-year was 16. Oral ste- Macrolide antibiotics are indicated for treatment because of roid use, antibiotic use, and addition of tiotropium also were their antibacterial effects. The class also has been associated significantly higher in the fluticasone/salmeterol groupP ( < with immunomodulatory and anti-inflammatory effects. 0.0001). Differences in the frequency of adverse effects were Macrolides reduce mucus, sputum production, and the not reported.40 percentage of neutrophils in pulmonary fluid, which may No randomized double-blind trials have compared decrease the amount of cytotoxic substances that cause budesonide/formoterol with fluticasone/salmeterol. A pre- pulmonary remodeling. Macrolides also may inhibit the vious retrospective 1-year study reported a 15% reduction in release of cytokines and TNF-alpha.44 COPD exacerbations with budesonide/formoterol compared Several small studies have yielded conflicting results with fluticasone/salmeterol (nonsignificant).41 The PATHOS regarding the use of macrolides to prevent acute COPD ex- study was a long-term, robust study in a large number of acerbations. A randomized, prospective, placebo-controlled patients and may have real-world implications. The publi- study recently was conducted to test the hypothesis that cation stated that patients who switched treatment during azithromycin 250 mg orally administered once daily reduces the course of chart review had a higher yearly exacerbation the frequency of COPD exacerbations when added to usual rate but did not show the supporting data. Recommending care. The study included 1,142 patients who were 40 years budesonide/formoterol over fluticasone/salmeterol for ini- or older and had a smoking history of 10 pack-years, clinical tial combination therapy in patients with moderate to severe diagnosis of COPD, and FEV1/FVC less than 70%. Patients COPD is reasonable. More data are needed to assess whether must have had a history of exacerbation within the previous switching from one combination to the other would be of year. Patients were excluded if they had a resting heart rate benefit. greater than 100 bpm, had a prolonged QTc interval (>450 ms), or were using medications that prolong the QTc inter- HMG-CoA reductase inhibitors in COPD val.45 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) re- The primary endpoint was time to first COPD exacerba- ductase inhibitors (statins) are indicated for the reduction tion. Median time to first exacerbation was 266 days among of serum cholesterol. Interest in the anti-inflammatory pleo- patients receiving azithromycin compared with 174 days in trophic effects of statins has been longstanding. In addition the placebo group (P < 0.001). The frequency of exacerbations to their cardiovascular benefit, evidence shows that statins also was significantly decreased in the azithromycin group. have strong immune-modulating effects in pulmonary cir- An increased incidence of colonization with macrolide-resis- culation. Statins are known to reduce neutrophil influx in tant organisms occurred in patients receiving azithromycin, the lung and inhibit the expression of many inflammatory and a statistically significant increase in hearing decrements mediators, such as C-reactive protein, TNF-alpha, and vari- was observed compared with the placebo group.45 ous cytokines, which are inversely related to FEV1. This in- A retrospective cohort from 2012 found a statistically hibition may delay inflammatory-mediated lung deteriora- significant increase in the risk of cardiovascular death as- tion in COPD.42 Several retrospective observational studies sociated with azithromycin compared with no antibiotics, have displayed beneficial effects of statin use for a number amoxicillin, or ciprofloxacin.46 Patients received only 5 days of different COPD outcomes, including exacerbation rate of therapy in the study. Albert et al.45 did not find any sig- and mortality. One large retrospective case–control study in nificant increase in cardiovascular events in the treatment 14,316 Taiwanese patients who were hospitalized for COPD group; however, patients with cardiovascular comorbidities exacerbations displayed a 30% decreased risk of COPD ex- were excluded. Azithromycin should not be used in patients acerbation with statin use.43 Currently, long-term prospective with a history of CVD for preventing exacerbation in COPD. trials assessing simvastatin, , and rosuvastatin for Azithromycin may be a viable option in patients without use in COPD are in progress.5 CVD for exacerbation prevention; however, further studies are needed to assess the frequency of hearing loss and bacte- rial resistance patterns. Macrolides are an important antibac- terial class in the treatment of pneumonia in patients with COPD. The clinical significance of resistance to this class re- mains unknown.

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Patient adherence As stated by former U.S. Surgeon General C. Everett Koop, such as HMG-CoA reductase inhibitors and macrolides to “Drugs don’t work if patients don’t take them.” Medication prevent COPD exacerbations. An extensive COPD pipeline adherence can be difficult in COPD because of the typical also exists. Regardless of the treatment approach, patient ad- age of affected patients and the mode of administration of herence is a critical factor in predicting success. Pharmacists the majority of the drugs. Studies have shown that better play a vital role in promoting patient adherence in order to medication adherence is associated with a decrease in hos- maximize therapeutic efficacy, leading to decreased morbid- pitalizations and improved quality of life.25 A subanalysis of ity and mortality and an improved quality of life. the TORCH (Towards a Revolution in COPD Health) study Answers to case study questions: 1, c; 2, c; 3, a; 4, b; 5, c; 6, d; 7, c; 8, showed that good adherence to COPD medication decreased d; 9, a; 10, b. mortality rates compared with poor adherence (26.4% vs. 11.3%).47 References Studies analyzing adherence in the COPD population are 1. National Heart, Lung, and Blood Institute. Morbidity and mortal- limited; however, data suggest that adherence is poor. A ret- ity: 2012 chart book on cardiovascular, lung, and blood diseases. rospective study conducted in 2,730 veterans with COPD re- Bethesda, MD: National Heart, Lung, and Blood Institute: ported an adherence of only 19.8% in patients taking inhaled 2009;59–60. 2. Vestbo J, Hurd SS, Agusti AG, et al. Global Strategy for the Diag- corticosteroids, 30.6% in patients taking inhaled long-acting nosis, Management, and Prevention of Chronic Obstructive Pul- beta agonists, and 25.6% in patients taking inhaled ipratro- monary Disease: GOLD executive summary. www.goldcopd.org/ pium. Although the study was unable to determine the exact uploads/users/files/GOLD_Report_2013_Feb20.pdf. Accessed cause of poor adherence, it did state that past adherence is- June 10, 2013. sues to medications in one class led to adherence issues if the 3. Hoyert DL, Xu J. Deaths: preliminary data for 2011. www.cdc.gov/ drug was changed to another in the same class.48 Multiple- nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed June 10, 2013. inhaler use also has been associated with higher rates of non- 4. Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: sys- adherence compared with single-inhaler use. A combination tematic review and meta-analysis. Eur Respir J. 2006;28(3):523– product should be recommended whenever possible in order 32. to improve adherence rates. 5. Gross NJ. Novel anti-inflammatory therapies for COPD. Chest 2012;142(5):1300–7. Pharmacists play a huge role in improving treatment 6. Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory ill- adherence in COPD. Patients need to be taught how to use ness in patients with COPD and the effectiveness of influenza vac- their devices, and pharmacists should ensure that patients cination: a randomized controlled study. Chest. 2004;125(6):2011– can demonstrate proper use of devices before leaving the 20. practice site. Studies have shown that if patients feel their in- 7. Spiriva [package insert]. Ridgefield, CT: Boehringer Ingelheim; haler is not working, adherence is more likely to be poor.49 2012. Pharmacists can observe and improve inhalation technique, 8. Wilchesky M, Ernst P, Brophy JM, et al. Bronchodilator use and help find discounts to offset cost, and reassure patients about the risk of arrhythmia in COPD. Part 2: reassessment in the larger what to expect regarding adverse effects. Quebec cohort. Chest. 2012;142(2):305–11. In 2010, a group of 55 community pharmacist conducted 9. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and flutica- sone propionate and survival in chronic obstructive pulmonary a study in 597 patients with asthma or COPD. Pharmacists disease. N Engl J Med. 2007;356(8):775–89. interviewed and checked inhalation technique in patients 10. Short PM, Williamson PA, Elder DH, et al. The impact of tiotropium at baseline, corrected any errors, and reassessed technique on mortality and exacerbations when added to inhaled cortico- 4 to 6 weeks later. At baseline, 78.9% of patients made at least steroids and long-acting beta-agonist therapy in COPD. Chest. one mistake when using their inhaler. When the patients re- 2012;141(1):81–6. turned 4 to 6 weeks after they were educated, the percent 11. Drummond MB, Dasenbrook EC, Pitz MW, et al. Inhaled cor- was reduced to 28.3%.50 Pharmacists can have a major impact ticosteroids in patients with stable chronic obstructive pulmo- on inhaler technique after spending time with a patient just nary disease: a systematic review and meta-analysis. JAMA. once, which can ultimately lead to improved medication ad- 2008;300(20):2407–16. herence and quality of life. 12. Daliresp [package insert]. St. Louis, MO: Forest; 2011. 13. Forest. Roflumilast in chronic obstructive pulmonary disease (COPD) patients treated with fixed dose combinations of long- Conclusion acting beta2-agonist (LABA) and inhaled corticosteroid (ICS). COPD is a major cause of morbidity and mortality in the Unit- www.clinicaltrials.gov/ct2/show/NCT01443845. Accessed June ed States. The GOLD guidelines continue to be the standard 10, 2013. for medication management for COPD. Aclidinium bromide, 14. Price D, Chisholm A, Ryan D, et al. The use of roflumilast indacaterol maleate, and fluticasone furoate/vilanterol are in COPD: a primary care perspective. Prim Care Respir J. new medications that have been approved since the guide- 2010;19(4):342–51. lines were published. These drugs may be viable treatment 15. Theo-24 [package insert]. Smyrna, GA: UCB; 2006. options based on patient-specific factors in managing COPD. 16. Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmo- Research is ongoing for the use of currently approved agents nary disease. Eur Respir J. 2007;29(6):1224–38. www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 61 CPE copd update

17. Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in 34. GlaxoSmithKline. FDA Advisory Committee recommends approval chronic obstructive pulmonary disease exacerbation requiring me- in US of umeclidinium/vilanterol for the treatment of COPD. www. chanical ventilation: a randomized placebo-controlled trial. Lancet. gsk.com/media/press-releases/2013/fda-advisory-committee- 2001;358(9298):2020–5. recommends-approval-in-us-of-umeclidinium.html. Accessed June 18. Tudorza Pressair [package insert]. St. Louis, MO: Forest; 2012. 11, 2013. 19. Fores. Efficacy and safety study of two fixed-dose combinations 35. Clarke T. FDA panel supports approval of Glaxo lung drug Anoro. of aclidinium bromide with formoterol fumarate compared with www.reuters.com/article/2013/09/10/us-glaxosmithkline-copd- aclidinium bromide, formoterol fumarate and placebo. http://clini- idUSBRE98915P20130910. Accessed June 11, 2013. caltrials.gov/show/NCT01049360. Accessed June 10, 2013. 36. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salme- 20. Arcapta Neohaler [package insert]. East Hanover, NJ: Novartis; terol for the prevention of exacerbations of COPD. N Engl J Med. 2012. 2011;364(12):1093–103. 21. Donohue JF, Fogarty C, Lötvall J, et al. Once-daily bronchodila- 37. Gershon A, Croxford R, To T, et al. Comparison of inhaled long- tors for chronic obstructive pulmonary disease: indacaterol versus acting beta-agonist and anticholinergic effectiveness in older pa- tiotropium. Am J Respir Crit Care Med. 2010;182(2):155–62. tients with chronic obstructive pulmonary disease: a cohort study. 22. Dahl R, Chung KF, Buhl R, et al. Efficacy of new once-daily Ann Intern Med. 2011;154(9):583–92. long-acting inhaled beta2-agonist indacaterol versus twice-daily 38. Hawkins NM, Petrie MC, Macdonald MR, et al. Heart failure and formoterol in COPD. Thorax. 2010;65(6):473–9. chronic obstructive pulmonary disease: the quandary of beta- 23. Korn S, Kerwin E, Atis S, et al. Indacaterol once-daily provides blockers and beta-agonists. J Am Coll Cardiol. 2011;57(21):2127– superior efficacy to salmeterol twice-daily in COPD: a 12-week 38. study. Respir Med. 2011;105(5):719–26. 39. Spiriva [package insert]. Ridgefield, CT: Boehringer Ingelheim; 24. Mahler DA, D’Urzo A, Bateman ED, et al. Concurrent use of inda- 2012. caterol plus tiotropium in patients with COPD provides superior 40. Larsson K, Janson C, Lisspers K, et al. Combination of bronchodilation compared with tiotropium alone: a randomized, budesonide/formoterol more effective than fluticasone/salmeterol double-blind comparison. Thorax. 2012;67(9):781–8. in preventing exacerbations in chronic obstructive pulmonary 25. Hodder R, Price D. Patient preferences for inhaler devices in disease: the PATHOS study. J Intern Med. 2013;273(6):584–94. chronic obstructive pulmonary disease: experience with Respimat 41. Blais L, Forget A, Ramachandran S. Relative effectiveness of Soft Mist Inhaler. Int J Chron Obstruct Pulmon Dis. 2009;4:381– budesonide/formoterol and /salmeterol 90. in a 1-year, population-based, matched cohort study of patients 26. Van Noord JA, Cornelissen PJ, Aumann JL, et al. The efficacy of with chronic obstructive pulmonary disease (COPD): effect on tiotropium administered via Respimat Soft Mist Inhaler or Handi- COPD-related exacerbations, emergency department visits and Haler in COPD patients. Respir Med. 2009;103(1):22–9. hospitalizations, medication utilization, and treatment adherence. 27. Combivent Respimat [package insert]. Ridgefield, CT: Boehringer Clin Ther. 2010;32(7):1320–8. Ingelheim; 2012. 42. Young RP, Hopkins R, Eaton TE. Pharmacological ac- 28. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily in- tions of statins: potential utility in COPD. Eur Respir Rev. haled fluticasone furoate and vilanterol versus vilanterol only for 2009;18(114):222–32. prevention of exacerbations of COPD: two replicate double-blind, 43. Wang MT, Lo YW, Tsai CL, et al. Statin use and risk of COPD ex- parallel-group, randomized controlled trials. The Lancet Respira- acerbation requiring hospitalization. Am J Med. 2013;126(7):598– tory Medicine. 2013;1(3):210–23. 606.e2. 29. Luik S. Striverdi Respimat (olodaterol) inhalation spray: United 44. López-Boado YS, Rubin BK. Macrolides as immunomodulatory States Food and Drug Administration Pulmonary-Allergy Drugs medications for the therapy of chronic lung diseases. Curr Opin Advisory Committee. www.fda.gov/downloads/AdvisoryCommit- Pharmacol. 2008;8(3):286–91. tees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrug- 45. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention sAdvisoryCommittee/UCM337988.pdf. Accessed June 11, 2013. of exacerbations of COPD. N Engl J Med. 2011;365(8):689–98. 30. Boehringer Ingelheim. Tiotropium + olodaterol fixed dose combina- 46. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of tion (FDC) versus tiotropium and olodaterol in chronic obstruc- cardiovascular death. N Engl J Med. 2012;366(20):1881–90. tive pulmonary disease (COPD). http://clinicaltrials.gov/show/ 47. Vestbo J, Anderson JA, Calverley PM, et al. Adherence to inhaled NCT01431287. Accessed June 11, 2013. therapy, mortality, and hospital admission in COPD. Thorax. 31. D’Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of 2009;64(11):939–43. once-daily NVA237 in patients with moderate-to-severe COPD: the 48. Huetsch JC, Uman JE, Udris EM, Au DH. Predictors of adherence GLOW1 trial. Respir Res. 2011;12:156. to inhaled medications among veterans with COPD. J Gen Intern 32. Kerwin E, Hébert J, Gallagher N, et al. Efficacy and safety of Med. 2012;27(11):1506–12. NVA237 versus placebo and tiotropium in patients with COPD: the 49. Mäkelä MJ, Backer V, Hedegaard M, Larsson K. Adherence to GLOW2 study. Eur Respir J. 2012;40(5):1106–14. inhaled therapies, health outcomes and costs in patients with 33. Novartis. Safety and tolerability of QVA149 (indacaterol/glycopyr- asthma and COPD. Respir Med. 2013;107(10):1481–90. rolate) compared to placebo and to indacaterol in patients with 50. Hämmerlein A, Müller U, Schulz M. Pharmacist-led interven- moderate to severe stable chronic obstructive pulmonary disease tion study to improve inhalation technique in asthma and COPD (COPD). http://clinicaltrials.gov/show/NCT00558285. Accessed patients. J Eval Clin Pract. 2011;17(1):61–70. June 11, 2013.

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CPE assessment Instructions: This exam must be taken online; please see “CPE information” for further instructions. The online system will present these questions in random order to help reinforce the learning opportunity. There is only one correct answer to each question.

1. A patient tells you that he has been diagnosed with 5. A patient comes to the pharmacy with a prescription GOLD group A chronic obstructive pulmonary dis- for clarithromycin. You notify their physician to alert ease. Which of the following medication classes is in- them about a potential interaction with which of the dicated for this stage? following? a. Inhaled long-acting anticholinergic a. Fluticasone/salmeterol b. Inhaled corticosteroid b. Aclidinium c. Inhaled short-acting beta-2 agonist c. Tiotropium d. Oral phosphodiesterase-4 inhibitor d. Ipratropium

2. The most common adverse effect associated with use 6. Roflumilast belongs to which of the following classes of tiotropium is: of medications? a. Pharyngitis. a. Long-acting beta-2 agonist b. Dry mouth. b. Xanthine derivative c. Decreased bone mineral density. c. Phosphodiesterase-4 inhibitor d. Urinary incontinence. d. Corticosteroid

3. Which of the following medications is a short-acting 7. Which of the following medications would you be beta-2 agonist? hesitant to recommend for patients with epilepsy? a. Salmeterol a. Aclidinium b. Indacaterol b. Theophylline extended release c. Arformoterol c. Fluticasone/vilanterol d. Levalbuterol d. Ipratropium bromide and albuterol

4. A patient has been stable on salmeterol 50 µg every 8. Which of the following nebulizer treatment is indi- 12 hours and fluticasone 220 µg every 12 hours for the cated for patient who are having acute, severe dyspnea previous 3 months. Which of the following would you due to a COPD exacerbation? recommend? a. Arformoterol 15 µg a. Continue the current regimen b. Formoterol 20 µg b. Add tiotropium 18 µg daily c. Budesonide 0.5 mg c. Decrease salmeterol to 50 µg daily d. Albuterol/ipratropium 0.5/2.5 mg d. Add theophylline extended release 300 mg orally daily

CPE information To obtain 2.0 contact hours (0.2 CEUs) of CPE credit for this activity, you must complete the online Assessment and Evaluation. A Statement of Credit will be awarded for a passing grade of 70% or better on the Assessment. You will have two opportunities to successfully complete the CPE Assessment. Pharmacists who successfully complete this activity before October 1, 2016, can receive CPE credit. Your Statement of Credit will be available upon successful completion of the Assessment and Evaluation and will be stored in your ‘My Training’ page and on CPE Monitor for future viewing/printing.

CPE instructions: 1. Log in or create an account at pharmacist.com and select LEARN from the top of the page; select Continuing Education, then Home Study CPE to access the Library. 2. Enter the title of this article or the ACPE number to search for the article, and click on the title of the article to start the home study. 3. To receive CPE credit, select Enroll Now or Add to Cart from the left navigation and successfully complete the Assessment (with random- ized questions), Learning Evaluation, and Activity Evaluation. 4. To get your Statement of Credit, click “Claim” on the right side of the page. You will need to provide your NABP e-profile ID number to obtain and print your Statement of Credit. Live step-by-step assistance is available Monday through Friday from 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected].

www.pharmacytoday.org NOVEMBER 2013 • PharmacyToday 63 CPE copd update

9. Aclidinium bromide should be used in caution in pa- 16. Glycopyrronium bromide has a similar mechanism of tients with: action to which of the following? a. Depression. a. Fluticasone b. Glaucoma. b. Ciclesonide c. Hypertension. c. Aclidinium d. Atrial fibrillation. d. Albuterol

10. Aclidinium bromide is advantageous over tiotropium 17. A patient who is currently managed with only a rescue because it: inhaler presents with a chronic obstructive pulmonary a. Is less likely to cause hypersensitivity reactions. disease exacerbation. Comorbidities include benign b. Has a more convenient dosing regimen. prostatic hyperplasia treated with and sei- c. Does not require unwrapping and loading a capsule zures. Which of the following long-acting bronchodi- into a device. lators would you recommend? d. Has fewer adverse effects. a. Tiotropium 80 µg inhaled daily b. Formoterol 12 µg inhaled every 12 hours 11. A patient has severe osteoarthritis and difficulty using c. Fluticasone/salmeterol 250/50 µg inhaled b.i.d. his hands. Which of the following medications would d .Fluticasone 440 µg inhaled every 12 hours you be least likely to recommend? a. Roflumilast 18. Your patient continues to have chronic obstructive b. Indacaterol pulmonary disease exacerbations in spite of a current c. Formoterol/mometasone regimen of indacaterol 75 µg inhaled once daily. The d. Beclomethasone physician would like to add a steroid. You recommend: a. Adding fluticasone 110µ g inhaled every 12 hours. 12. A patient presents a new prescription for indacaterol 75 b. Adding tiotropium 80 µg inhaled once daily. µg inhaled once daily. Which of the following medica- c. Changing to budesonide/formoterol 160/4.5 µg in- tions in the patient’s profile would require you to noti- haled twice daily. fy the patient’s physician about a potential interaction? d. Changing to fluticasone/salmeterol 250/50 µg in- a. Simvastatin 80 mg haled twice daily. b. Sertraline 50 mg c. Alprazolam 0.25 mg 19. Which of the following medications should be used in d. 25 mg caution in patients who have chronic obstructive pul- monary disease and a history of atrial fibrillation? 13. Your patient is currently taking budesonide/formoterol a. Azithromycin for managing chronic obstructive pulmonary disease. b. Rosuvastatin You notice that they are refilling their prescription ev- c. Aclidinium ery 60 days. To improve adherence, you recommend: d. Ciclesonide a. Formoterol/mometasone 200 µg/10 µg inhaled b.i.d. b. Flucatisone/vilanterol 100 µg/25 µg inhaled daily. 20. Patients with chronic obstructive pulmonary disease c. Ciclesonide 80 µg inhaled b.i.d. are less likely to adhere to their regimens if they are d. Indacaterol 75 µg inhaled daily. taking: a. Multiple inhalers. 14. Which of the following medications has the same b. One inhaler twice daily. mechanism of action as fluticasone/vilanterol? c. A combination product. a. Formoterol/mometasone d. An oral medication. b. Budesonide c. Indacaterol d. Simvastatin

15. Patients taking albuterol/ipratropium (Combivent Respimat—Boehringer Ingelheim) must load a drug cartridge into the device and give the inhaler an expi- ration date of: a. 28 days. b. 3 months. c. 6 months. d. 1 year.

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