FDA Approves Stiolto Respimat (tiotropium bromide and olodaterol) Inhalation Spray for COPD

Boehringer Ingelheim today announced that the U.S. Food and Drug Administration (FDA) approved once-daily Stiolto Respimat (tiotropium bromide and olodaterol) Inhalation Spray. It has been approved as a long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Stiolto Respimat is not indicated to treat asthma or acute deterioration of COPD.
COPD, which includes chronic bronchitis and emphysema, is a serious but treatable lung disease. More than 15 million Americans have been told that they have COPD, but as many as 45 percent of the total estimated COPD cases in the U.S. remain undiagnosed. Patients are typically diagnosed when lung function is already significantly impaired. COPD symptoms can negatively impact a patient’s ability to breathe especially when performing daily activities.

“A recent review of landmark studies indicates that loss of lung function is more accelerated in the early stages of COPD. While no treatment slows the rate of decline, maintenance treatment with Stiolto Respimat initiated at the time of diagnosis will improve lung function,” said Danny McBryan, MD, vice president, Clinical Development & Medical Affairs, Respiratory, Boehringer Ingelheim Pharmaceuticals, Inc. Lung function was measured by trough FEV11 and FEV1 AUC0-3h.2
About Stiolto Respimat
“Stiolto Respimat is a COPD maintenance treatment proven to be more effective than either Spiriva or olodaterol alone, with a comparable safety profile,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Patients may appreciate the benefits of a maintenance medication that improves lung function within five minutes, lasts all day and reduces the use of rescue inhalers.”

Stiolto Respimat does not replace the use of a rescue inhaler.

The pivotal trials for Stiolto Respimat evaluated more than 5,000 COPD patients and showed it provides statistically significant improvements in lung function (trough FEV1 and FEV1 AUC0-3h) at 24 weeks versus tiotropium and olodaterol alone. These 52-week Phase III TONADOTM 1&2 trials (NCT01431274/NCT01431287) were randomized, double-blind, active-controlled trials that compared Stiolto Respimat to tiotropium Respimat 5 mcg and olodaterol Respimat 5 mcg. Both trials were part of the TOviTO® clinical trial program involving more than 15,000 COPD patients worldwide. Stiolto Respimat showed a safety profile similar to tiotropium or olodaterol alone.

Long-acting beta2-adrenergic agonists, such as olodaterol, one of the active ingredients in Stiolto Respimat, increase the risk of asthma-related death. Stiolto Respimat is not indicated for asthma and should not be initiated in acutely deteriorating COPD patients or for the relief of acute symptoms. Stiolto Respimat is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product. As with other inhaled medicines, Stiolto Respimat may cause paradoxical bronchospasm that may be life-threatening. The most common adverse reactions were nasopharyngitis, cough and back pain.

“Stiolto Respimat produced greater lung function improvements in terms of FEV1 compared to tiotropium and olodaterol alone in patients with COPD across a range of disease severities (GOLD 2 to 4),” said Richard Casaburi, MD, PhD, professor and associate chief, Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center. “As a clinician, I am pleased to have a new treatment option to offer my patients.” Tiotropium is a long-acting anticholinergic maintenance therapy and the active ingredient in Spiriva Respimat (tiotropium bromide) Inhalation Spray and Spiriva HandiHaler (tiotropium bromide inhalation powder). Since its approval more than 10 years ago, Spiriva has extensive clinical experience with over 40 million patient-years worldwide. Spiriva is the most prescribed COPD maintenance treatment in the U.S. and worldwide.

Olodaterol, approved for COPD patients as STRIVERDI® Respimat (olodaterol) Inhalation Spray, is a long-acting beta2-agonist maintenance treatment that improves airflow within five minutes after the first dose. Olodaterol does not replace the use of a rescue inhaler.

About the Respimat Inhaler
Stiolto is administered via Respimat, the platform inhaler for the Boehringer Ingelheim respiratory therapies, including approved and investigational therapies. Respimat is the only inhaler that actively delivers a slow-moving mist that helps patients inhale the medication.

The Respimat inhaler delivers medication independent of inspiratory effort. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as coordination between actuation of the inhaler and inspiration through the delivery system. The duration of inhalation should be at least as long as the spray duration (1.5 seconds).

Indication for Stiolto Respimat
Stiolto Respimat (tiotropium bromide and olodaterol) Inhalation Spray is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA), indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations of Use

Stiolto is NOT indicated to treat acute deterioration of COPD and is not indicated to treat asthma.

Important Safety Information for Stiolto Respimat

Long-acting beta2-adrenergic agonists (LABA) such as olodaterol, one of the active ingredients in Stiolto Respimat, increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of all LABA, including olodaterol, one of the active ingredients in Stiolto Respimat. The safety and efficacy of Stiolto Respimat in patients with asthma have not been established. Stiolto Respimat is not indicated for the treatment of asthma.


All LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. Stiolto is contraindicated in patients with hypersensitivity to tiotropium, ipratropium (atropine derivatives), olodaterol, or any component of this product.

In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported. Hypersensitivity reactions were also reported in clinical trials with Stiolto.

Warnings and Precautions

Stiolto should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition, or used as rescue therapy for acute symptoms. Acute symptoms should be treated with an inhaled short-acting beta2-agonist. Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should discontinue the regular use of these drugs and use them only for acute respiratory symptoms.

Stiolto should not be used more often or at higher doses than recommended, or in conjunction with other LABA as an overdose may result.

Immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, or itching may occur after administration of Stiolto. If such a reaction occurs, discontinue therapy with Stiolto and consider alternative treatments. Patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to Stiolto.

If paradoxical bronchospasm occurs, Stiolto should be discontinued immediately.

Stiolto can produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms. If such effects occur, Stiolto may need to be discontinued.

Use caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a physician immediately if signs or symptoms of acute narrow-angle glaucoma develop (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

Use with caution in patients with urinary retention, which can be associated with symptoms like difficulty passing urine and painful urination in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Patients with moderate to severe renal impairment (creatinine clearance of ≤60 mL/min) treated with Stiolto should be monitored closely for anticholinergic side effects.

Be alert to hypokalemia, which has the potential to produce adverse cardiovascular effects. Be alert to hyperglycemia.

Adverse Reactions

The most common adverse reactions with Stiolto (>3% incidence and higher than any of the comparators – tiotropium and/or olodaterol) were: nasopharyngitis, 12.4% (11.7%/12.6%), cough, 3.9% (4.4%/3.0%), and back pain, 3.6% (1.8%/3.4%).

Drug Interactions

Use caution if administering adrenergic drugs because sympathetic effects of olodaterol may be potentiated.

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol.

Beta agonists, such as olodaterol, can acutely worsen the ECG changes and/or hypokalemia that may result from administration of non-potassium sparing diuretics. The action of adrenergic agents on the cardiovascular system may be potentiated by monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval. Therefore beta-agonists should be used with extreme caution in patients being treated with these drugs. Drugs that prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.

Beta-blockers should be used with caution as they can inhibit the therapeutic effect of beta agonists which may produce severe bronchospasms in patients with COPD. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardio selective beta-blockers could be considered, although they should be administered with caution.

Avoid co-administration of Stiolto with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Stiolto is for oral inhalation only. The Stiolto cartridge is only intended for use with the Stiolto Respimat inhaler.

Inform patients not to spray Stiolto into the eyes.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

About COPD
Chronic obstructive pulmonary disease (COPD) is a term including chronic bronchitis and/or emphysema. This disease can make breathing harder because less air is able to flow in and out of the lungs. Chronic lower respiratory diseases, which include COPD, are the third leading cause of death in the United States, and approximately 15 million Americans have been told by a healthcare provider that they have COPD.

The most common symptom of COPD is shortness of breath, especially with physical activities. Coughing, with or without mucus production, is also a common symptom of COPD. These symptoms can be misunderstood as signs of aging. COPD is usually associated with progressive airway damage and loss that cause breathing to get more difficult.

Leading Respiratory Forward
Through research, treatments and patient-centric support services, the Boehringer Ingelheim (BI) lung health portfolio is designed to help address the challenges people living with a lung disease face every day. Leveraging the company’s cutting edge science and leadership in chronic obstructive pulmonary disease (COPD), BI is researching new treatment approaches where needs persist. It is the company’s goal to make a difference in the lives of patients with COPD, asthma, lung cancer, idiopathic pulmonary fibrosis and other respiratory diseases.

More Than Just Reassurance on Tiotropium Safety.

Since its registration in 2002, a dry-powder formulation of tiotropium delivered by a HandiHaler inhalation device has consistently been recommended in clinical-practice guidelines as first-line maintenance bronchodilator therapy for chronic obstructive pulmonary disease (COPD). This recommendation is based on the efficacy of tiotropium in improving lung function, exercise capacity, and quality of life and in reducing moderate and severe COPD exacerbations.

The safety reputation of tiotropium as delivered by dry-powder inhalation remained relatively unblemished until its successor, tiotropium delivered by a soft-mist Respimat inhaler, underwent clinical trials. Despite the clear efficacy of the Respimat formulation, post hoc pooled safety analyses showed an increased rate of death from any cause in patients treated with the Respimat inhaler at a dose of 5 μg of tiotropium, as compared with placebo, an effect that was particularly evident in patients with a history of cardiac arrhythmias.1 All of a sudden, the previous hints at the possibility of cardiovascular risk for ipratropium and tiotropium held more water and needed to be addressed, especially given the widespread use of this drug, the increasing global prevalence of COPD, the guideline recommendations for tiotropium as a first-line COPD treatment, and the high burden of coexisting cardiac conditions and deaths in the COPD population.

Multiple meta-analyses and observational database studies did not resolve the issue, and regulators issued warnings.2 In a systematic review of pooled data from 17 trials (enrolling a total of 13,645 participants), patients with COPD who received inhaled anticholinergic medications had higher rates of myocardial infarction, stroke, and death from cardiovascular causes or a composite of all three outcomes than those receiving placebo or an active control, with a relative risk of 1.60 (95% confidence interval [CI], 1.22 to 2.10; P<0.001) for cardiovascular events and 1.29 (95% CI, 1.00 to 1.65; P=0.05) for death from any cause.3 However, several other meta-analyses showed no evidence of increased rates of cardiovascular events or death.4,5 Most important, data from the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial6 were consistent with a reduction in all-cause mortality in patients with COPD who were receiving tiotropium, as compared with those receiving placebo, during a 4-year period, with a protective effect for cardiac mortality. A subsequent meta-analysis of 30 trials including UPLIFT (enrolling a total of 19,545 participants) showed that tiotropium was associated with reduced rates of death from any cause and from cardiac causes and of cardiovascular events.5However, the soft-mist Respimat inhaler remained under a cloud, with a systematic review reporting a 50% increased risk of death in 2011.1 Although a Cochrane review of 22 studies (enrolling a total of 23,309 participants) did not show an increased risk of death from any cause associated with dry-powder tiotropium HandiHaler, it showed significantly more deaths associated with the soft-mist Respimat inhaler (Peto odds ratio, 1.47; 95% CI, 1.04 to 2.08), with placebo used as the control in the two comparisons.7

Large randomized, controlled trials are usually designed and powered to meet statistical certainty for efficacy end points that have clinical significance for clinicians, patients, or regulators. But when efficacy has been established and safety is then questioned, it is sadly not the rule that rigorous, well-powered studies are conducted to address these concerns. Most studies are grossly underpowered for safety outcomes, and adverse events are listed with small numbers to which only an eyeball test can be applied. The reporting of “no difference” between adverse events in an intervention group and those in a control group is hardly ever questioned, even though it rarely has statistical validity.

In the Tiotropium Safety and Performance in Respimat (TIOSPIR) study,8 Wise et al. turn this tradition on its head by seriously addressing the widely expressed concern about the safety of tiotropium Respimat. In this large clinical trial, now reported in the Journal, involving 17,135 patients with COPD for a median duration of 835 days, the investigators compared the safety and efficacy of once-daily tiotropium doses of 2.5 μg and 5 μg delivered by Respimat with a once-daily dose of 18 μg of tiotropium delivered by HandiHaler. Primary end points were the rate of death (noninferiority study for both doses of Respimat vs. HandiHaler) and the rate of the first COPD exacerbation (superiority study for Respimat 5 μg vs. HandiHaler). There was no significant difference among the three study groups with respect to death (hazard ratio for Respimat 5 μg vs. Handihaler, 0.96; 95% CI, 0.84 to 1.09; hazard ratio for Respimat 2.5 μg vs. Handihaler, 1.0; 95% CI, 0.87 to 1.14) or the first exacerbation (hazard ratio for Respimat 5 μg vs. HandiHaler, 0.98; 95% CI, 0.93 to 1.03). Patients with stable cardiac disease were included in the study, and there was no significant difference in mortality for those with a history of arrhythmia. The incidences of major cardiovascular adverse events were similar in the three study groups.

These results address several previous criticisms leveled against randomized, controlled trials and meta-analyses that did not identify an increased risk of death (or that showed a risk reduction) associated with tiotropium. A major concern was the possibility that the failure to identify a risk of death in some meta-analyses was due to the exclusion of patients with a cardiac history, especially arrhythmia or recent myocardial infarction, or those with other serious coexisting illnesses who might be at risk because of participation in the trial. In the TIOSPIR study, the clinical characteristics, coexisting illnesses, and coprescribed medications of the recruited patients suggest they do represent typical patients with symptomatic COPD, and the rate of follow-up was 99.7%. However, it is important to note that the absence of a placebo group in this study has implications for its interpretation and that it cannot be concluded from these results that tiotropium reduces mortality in patients with COPD.

The rigor, careful conduct, scrupulous follow-up of patients, and use of clinically appropriate entry criteria in this study will reassure many clinicians who may have had concerns about the narrow focus of some COPD trials. The global recruitment, fast completion, and clear outcomes of the trial should also encourage all those who fear that real-world studies enrolling patients who truly reflect typically heterogeneous populations and phenotypes will produce messy, uninterpretable results. This study clears the air regarding the safety of tiotropium delivered by Respimat and at the same time establishes a high standard for clinical trials involving patients with COPD, particularly studies that focus on patient safety.


Source: NEJM



Tiotropium Prevents Exacerbations in Some Patients with Severe Asthma.

In patients with poorly controlled asthma, this agent might be a reasonable option.

Some patients with asthma continue to experience poor lung function despite receiving long-acting β-agonists (LABAs) in combination with inhaled corticosteroids (ICS). Tiotropium is a long-acting anticholinergic (approved for chronic obstructive pulmonary disease) that has shown promise in short-term trials for treating asthmatic patients (JW Gen Med Jun 14 2011).

In two replicate, industry-sponsored, randomized trials, 912 adult patients received tiotropium or placebo. All patients experienced at least one severe exacerbation in the previous year and had persistent airflow limitation (mean post-bronchodilator forced expiratory volume in 1 second [FEV1], 62% of predicted), despite therapy with high-dose ICS and LABAs, which were continued during the study. At 24 weeks, lung function in the tiotropium group had increased modestly (roughly 100 cc) from baseline FEV1. The interval at which 25% of patients had experienced severe exacerbations was significantly longer with tiotropium than with placebo (282 vs. 226 days). At 48 weeks, the number needed to treat with tiotropium to prevent 1 severe exacerbation was 15. Asthma symptom scores did not reach the predefined clinically significant endpoint. Adverse events were similar in both groups.

Comment: Overall, improvement in lung function and exacerbations was modest when tiotropium was added to therapy in patients who already were receiving high-dose ICS and LABAs. That said, we have little else to offer patients with severe asthma and fixed obstruction. Although tiotropium is not FDA-approved for asthma, I think it is a reasonable option for patients who continue to have exacerbations that require oral corticosteroids or hospitalizations despite maximal asthma therapy. In an accompanying editorial, the writer cautions against extending this finding to all asthmatics, because fixed obstruction might share features with COPD and thus be responsive to the anticholinergic effect. Also, she points out that tiotropium (especially in the fine-mist device used in this study versus the dry-powder device we have in the U.S.) might contribute to risk for death from cardiovascular causes and cautions against its use in patients with cardiovascular disease.

 David J. Amrol, MD

Dr. Amrol is an Associate Professor of Clinical Internal Medicine and Director of the Division of Allergy and Immunology at the University of South Carolina School of Medicine in Columbia.

Source: Journal Watch General Medicine