Indacaterol (ARCAPTA NEOHALER): The Wrong Choice for COPD

Chronic obstructive pulmonary disease (COPD) affects approximately 15 million Americans, and more than 140,000 people in the U.S. die each year from the disease.[1] It also is estimated that millions more have the disease without knowing it.[2]

Indacaterol (ARCAPTA NEOHALER) was approved by the Food and Drug Administration (FDA) in 2011 at a dosage of 75 micrograms (mcg) daily for the long-term treatment of breathing problems due to airway obstruction in patients with COPD.[3] The drug is a member of a class of medications known as long-acting beta2 agonists (LABAs).[4] These drugs are bronchodilators that work by relaxing the muscles in the airways of the lungs, causing them to expand and resulting in improved airflow.

Public Citizen's Health Research Group has classified indacaterol as Do Not Use because the lowest dosage that provides the desired benefits with the best safety profile has never been established and the drug offers no clinically significant advantages over other available FDA-approved LABAs.

COPD overview

COPD is a chronic, progressive lung disease that includes two conditions: chronic bronchitis (in which the airways become inflamed) and emphysema (in which the lung's air sacs are permanently damaged). It is characterized by the narrowing of airways, caused by either blockage or swelling, making it difficult to breathe. Other symptoms include persistent cough, increased mucus production, wheezing and chest tightness.[5]

Cigarette smoking is the leading cause of COPD, accounting for 85 to 90 percent of cases.[6]

Other risk factors for COPD include inhalation of secondhand smoke, air pollution, exposure to workplace dusts and chemicals, and certain genetic traits.[7] Although there is no cure for COPD, current treatments are intended to slow the decline in lung function, improve symptoms, increase exercise tolerance and reduce the risk of exacerbations, which may lead to hospitalization.

Initial FDA rejection

In 2008, Novartis Pharmaceuticals first applied for FDA approval of indacaterol for treatment of COPD at proposed dosages of 150 mcg and 300 mcg once daily.[8]

In 2009, the FDA rejected the company's application because of safety concerns. In particular, the agency noted that during clinical trials, serious adverse cardiovascular events had occurred more frequently in COPD subjects who received indacaterol at the proposed doses than in those who received either a placebo or the FDA-approved LABA formoterol (FORADIL, PERFOROMIST).[9] The agency required that the company assess the safety and effectiveness of lower doses of the drug for treating COPD.

Effectiveness of indacaterol at lower doses

In 2010, Novartis applied for approval of indacaterol for treatment of COPD at dosages of 75 mcg and 150 mcg once daily, and the FDA subsequently approved the drug only at the lower dosage.

The effectiveness of the drug at the approved dosage of 75 mcg once daily was assessed in two 12-week randomized, placebo-controlled trials.[10] These trials together enrolled 641 subjects who were age 40 or older, had smoked on average one pack of cigarettes per day for at least 10 years and had met criteria for moderate-to-severe COPD. The indacateroltreated subjects had significantly improved lung function compared with those who received a placebo.[11] Importantly, these trials did not compare indacaterol with any other LABAs previously approved by the FDA.

More importantly, in its second application for approval of indacaterol, Novartis also presented data from another clinical trial that assessed the effectiveness of lower doses of indacaterol in 552 subjects with moderate-to-severe COPD who were age 40 or older and had smoked on average one pack of cigarettes per day for at least 10 years.[12] The subjects were randomly assigned to receive one of the following for 14 days: indacaterol, at a dosage of either 19, 38, 75 or 150 mcg once daily; the FDA-approved LABA salmeterol (SEREVENT) at the FDA-approved dosage of 50 mcg twice daily; or a placebo inhaler. The trial showed that subjects who received indacaterol at dosages of 38, 75 and 150 mcg once daily and those who received salmeterol had similar improvements in lung function after two weeks compared with those who received a placebo.

Use of indacaterol at a dosage of 38 mcg once daily (or perhaps other dosages lower than 75 mcg once daily), if effective with long-term use, likely would have a better safety profile than the FDA-approved dosage of 75 mcg once daily. For this reason, Public Citizen's Health Research Group urged the FDA in 2011 not to approve indacaterol.[13] Nevertheless, the FDA did not require Novartis to conduct additional clinical trials lasting longer than two weeks to assess the effectiveness and safety of indacaterol at dosages lower than 75 mcg once daily prior to approving the drug.

Adverse effects

Although LABAs are effective in treating COPD, they can increase the risk of asthma-related deaths. In 2009, the FDA specifically refused to approve indacaterol for the treatment of asthma because of concerns that it was associated with more frequent asthma-related deaths compared with salmeterol. [14]

When the drug was approved for treatment of COPD in 2011, the agency required that the product labeling for the drug include a black-box warning — the strongest type of safety warning the FDA can require — against the use of this drug for the treatment of asthma (see box below).[15]

The most common adverse effects of indacaterol are similar to those of other LABAs, which include cough, oropharyngeal pain, headache and nausea.[16]

Excessive use of indacaterol, particularly when used in combination with short-acting beta2 agonists or other LABAs, can result in serious, potentially fatal adverse cardiovascular effects.[17] Sudden hypersensitivity (allergic) reactions, leading to difficulty breathing; swelling of the tongue, lips and face; and hives also have been reported with indacaterol.

What You Can Do

You should only take LABAs if you are at high risk of COPD exacerbations, experience frequent symptoms or both. You should avoid starting indacaterol if you are not currently taking it. If you are already taking indacaterol, consult with your doctor about switching to either salmeterol or formoterol.

If you have COPD and you smoke, quitting smoking is the crucial, most effective way of slowing down disease progression and improving symptoms. Avoid chemical irritants that can lead to exacerbation of symptoms, such as secondhand smoke and air pollutants. In addition to drugs, pulmonary rehabilitation therapy such as exercise, nutritional counseling, breathing strategies, psychological counseling and education can help improve symptoms and quality of life.

References

[1] Centers for Disease Control and Prevention. COPD. November 27, 2018. https://www.cdc.gov/dotw/copd/. Accessed March 8, 2019.

[2] Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease (COPD). June 6, 2018. https://www.cdc.gov/copd/index.html. Accessed March 7, 2019.

[3] Food and Drug Administration. Letter to Novartis Pharmaceuticals Corporation approving NDA 022383/Orig-01. July 1, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000Approv.pdf. Accessed March 8, 2019.

[4] Sunovion Pharmaceuticals. Label: indacaterol (ARCAPTA NEOHALER). March 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e82416ba-23b9-4d40-a41d-baba8e11751b. Accessed March 8, 2019.

[5] National Institutes of Health, National Heart, Lung, and Blood Institute. COPD. https://www.nhlbi.nih.gov/health-topics/copd. Accessed March 11, 2019.

[6] American Lung Association. What causes COPD. March 13, 2018. https://www.lung.org/lung-health-and-diseases/lung-disease-lookup/copd/symptoms-causes-risk-factors/what-causes-copd.html. Accessed March 11, 2019.

[7] National Institutes of Health, National Heart, Lung, and Blood Institute. COPD. https://www.nhlbi.nih.gov/health-topics/copd. Accessed March 11, 2019.

[8] Food and Drug Administration. Complete response letter to Novartis Pharmaceuticals for NDA 022383. October 16, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000OtherActionLtr.pdf. Accessed March 11, 2019.

[9] Ibid.

[10] Food and Drug Administration. Summary review for application number: 022383Orig1s000. July 1, 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000SumR.pdf. Accessed March 11, 2019.

[11] Ibid.

[12] Food and Drug Administration. Medical review(s) for application number: 022383Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000MedR.pdf. Accessed March 12, 2019.

[13] Public Citizen. Letter to the FDA on indacaterol maleate (Arcapta Neohaler). March 16, 2011. https://www.citizen.org/our-work/health-and-safety/letter-fda-indacaterol-maleate-arcapta-neohaler. Accessed March 12, 2019.

[14] Food and Drug Administration. Complete response letter to Novartis Pharmaceuticals for NDA 022383. October 16, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000OtherActionLtr.pdf. Accessed March 11, 2019.

[15] Sunovion Pharmaceuticals. Label: indacaterol (ARCAPTA NEOHALER). March 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e82416ba-23b9-4d40-a41d-baba8e11751b. Accessed March 8, 2019.

[16] Sunovion Pharmaceuticals. Label: indacaterol (ARCAPTA NEOHALER). March 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e82416ba-23b9-4d40-a41d-baba8e11751b. Accessed March 8, 2019.

[17] Ibid.