SPIRIVA for COPD: Find Out Which Inhaler Is Safe

Chronic obstructive pulmonary disease (COPD) is a common progressive lung disease, usually caused by smoking, that blocks airflow and makes it difficult to breathe.[1] COPD includes two conditions: chronic bronchitis (in which the airways become inflamed) and emphysema (in which the lung’s air sacs are permanently damaged).

Tiotropium (SPIRIVA), a frequently prescribed drug administered via oral inhalers, belongs to a group of anticholinergic bronchodilator drugs known as long-acting muscarinic antagonists (LAMAs). It is used as long-term maintenance treatment for moderate to severe COPD: It can help manage the disease and decrease — but not treat — COPD flare-ups (when breathing suddenly gets much worse).[2]

It is available in two main formulations, both sold by the same drug company (Boehringer Ingelheim). The first is SPIRIVA HANDIHALER, a single-dose capsule administered via a dry-powder oral inhaler and approved by the Food and Drug Administration (FDA) in January 2004. The second is SPIRIVA RESPIMAT, a multidose soft-mist oral inhaler[3] approved in September 2014. (The FDA also approved SPIRIVA RESPIMAT for treatment of asthma in September 2015. This use is not addressed here.)

Research shows that the two tiotropium formulations have similar effectiveness. Yet multiple studies link RESPIMAT to higher risks for cardiovascular and overall deaths, compared with HANDIHALER. Therefore, Public Citizen’s Health Research Group has classified SPIRIVA RESPIMAT as Do Not Use. SPIRIVA HANDIHALER is the only LAMA we recommend for treating COPD. The evidence Several studies suggest that RESPIMAT increases cardiovascular and overall deaths compared with HANDIHALER or a placebo.

For example, a 2011 analysis of data pooled together from five clinical trials involving over 6,500 subjects linked RESPIMAT to a 52 percent increased risk of death compared with a placebo.[4] The study also suggested that this risk increases as the dose of tiotropium increases.

Similarly, a 2014 analysis published by the respected Cochrane Collaboration showed that RESPIMAT was associated with a 47 percent increased risk of death compared with a placebo.[5] This risk estimate was based on data from over 6,500 subjects in three trials. On the other hand, HANDIHALER was not associated with an increased risk of death compared to a placebo, based on data from 19 studies totaling over 16,700 subjects.

Moreover, a 2013 study that analyzed data from 42 clinical trials involving more than 50,000 COPD patients showed that RESPIMAT was associated with an increased risk of overall deaths when compared with a placebo, HANDIHALER or other COPD treatments.[6] In the head-to-head comparison with HANDIHALER, RESPIMAT had a 65 percent greater risk of overall deaths. This increased risk was more evident for cardiovascular deaths and among patients with severe COPD.

A controversial trial

Despite these studies, the FDA approved RESPIMAT[7] in 2014 (after rejecting it in 2008 because of safety concerns) based on results from the Tiotropium Safety and Performance in RESPIMAT (TIOSPIR) Trial.[8] This randomized clinical trial, which enrolled 17,000 COPD patients, found RESPIMAT was similar to, but not better than, SPIRIVA HANDIHALER in effectiveness and risk of overall death.

However, the trial has been criticized. First, trial researchers reported only the effect on overall deaths, which may have masked differences in deaths due to specific causes.[9] In fact, a subsequent independent analysis of the TIOSPIR Trial data revealed a statistically significant increase in the number of fatal heart attacks among RESPIMAT users compared with HANDIHALER users.[10] This finding is consistent with previous studies.[11]

Another criticism stems from the TIOSPIR Trial’s exclusion of patients with other diseases (such as moderate or severe kidney disease or unstable cardiovascular disease). The majority of patients with COPD have other serious diseases, which means the trial may not have adequately represented the patient population likely to use this drug, leading to an underestimation of the drug’s real-world risks.[12]

Indeed, evidence from an observational Dutch study of more than 11,000 patients showed that among patients with moderate to severe chronic kidney disease, RESPIMAT was associated with a 52 percent greater risk of death compared with HANDIHALER.[13] No increased risk with RESPIMAT was seen in patients without kidney disease. Likewise, in patients with cardiovascular diseases, RESPIMAT was associated with a 36 percent higher risk of death compared with HANDIHALER, whereas no increased risk with RESPIMAT was seen in those without cardiovascular diseases.[14]

RESPIMAT’s greater risk may seem surprising given that the approved tiotropium dose in RESPIMAT (5 micrograms) is lower than that in HANDIHALER (18 micrograms). However, RESPIMAT appears to be a more efficient drug delivery system than HANDIHALER, resulting in a higher amount of tiotropium being absorbed from the lungs into patients’ blood.[15]

Precautions and side effects

In opposition to its intended effect, tiotropium sometimes can cause sudden narrowing of airways (bronchospasm) and shortness of breath. If this occurs, patients should discontinue the drug and seek immediate medical care.

Tiotropium can cause allergic reactions, particularly among patients with a severe allergy to milk proteins. Symptoms of such reactions may include itching, rash and swelling of the lips, tongue or throat, possibly causing difficulty breathing or swallowing. Tiotropium can increase the risk of acute urinary retention (sudden inability to urinate), particularly among older men. Therefore, a male patient should check with his doctor before taking this drug if he has an enlarged prostate, a problem passing urine or a blockage in the bladder.

Patients with kidney disease should be monitored closely if they are put on tiotropium, because the kidneys play a major part in clearing the drug from the body.

Tiotropium can increase pressure in the eyes, causing glaucoma and resulting in pain, blurred vision, red eyes or seeing halos or colored images. If these symptoms occur, patients need to seek immediate medical help.

Tiotropium should not be taken together with other inhaled anticholinergic drugs (such as ipratropium [ATROVENT]), because this will increase the severity of these medications’ side effects. Examples of these adverse events include upper respiratory tract infection, dry mouth, sinus infection, sore throat, nonspecific chest pain, urinary tract infection, indigestion, runny nose, constipation and muscle weakness.

Tiotropium has not been studied in — and thus should be avoided by — pregnant and nursing women.

What You Can Do

If your doctor prescribes tiotropium to manage your COPD, ask for the HANDIHALER formulation. Due to safety concerns, we recommend that RESPIMAT not be used.

Our November 2015 issue has more information on long-term treatment options for COPD.[16]

Do not use tiotropium to treat sudden breathing problems. Instead, your doctor may prescribe other medications, such as a rescue inhaler, to use in these cases.[17]

References

[1] Centers for Disease Control and Prevention. Chronic Obstructive Pulmonary Disease (COPD). Who has COPD? http://www.cdc.gov/copd/index.html. Accessed April 13, 2016.

[2] SPIRIVA HANDIHALER (tiotropium bromide) inhalation powder: Drug label. December 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021395s040lbl.pdf. Accessed April 13, 2016.

[3] SPIRIVA RESPIMAT (tiotropium bromide) Inhalation Spray: Drug label. September 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021936s003lbl.pdf. Accessed April 14, 2016.

[4] Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: Systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215.

[5] Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;7:CD009285.

[6] Dong Y-H, Lin H-H, Shau W-Y, et al. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: Systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48-56.

[7] Center for Drug Evaluation and Research. September 2014. Application number 021936Orig1s000. Summary Review for Spiriva Respimat. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/021936Orig1s000SumR.pdf. Accessed April 13, 2016.

[8] Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-1501.

[9] Loke YK, Singh S, Furberg CD. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):480-481.

[10] Ibid.

[11] Mathioudakis AG, Chatzimavridou-Grigoriadou V, Evangelopoulou E,et al. Comparative mortality risk of tiotropium administered via handihaler or respimat in COPD patients: Are they equivalent? Pulm Pharmacol Ther. 2014;28(2):91-97.

[12] Ibid.

[13] Verhamme KM, van Blijderveen N, Sturkenboom MC. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):481-482.

[14] Verhamme KM, Afonso A, Romio S, et al. Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD. Eur Respir J. 2013;42(3):606-615.

[15] Singh S, Loke YK, Enright PL, and Furberg CD: Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: Systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215.

[16] Update on the long-term treatment of chronic obstructive pulmonary disease. Worst Pills, Best Pills News. November 2015. /newsletters/view/998. Accessed March 21, 2016.