FDA Approves Spiriva Respimat (Tiotropium) for the Maintenance Treatment of Asthma in Adults and Adolescents


Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) approved Spiriva Respimat for the long-term, once-daily, prescription maintenance treatment of asthma in people ages 12 and older. Spiriva Respimat is not a treatment for sudden asthma symptoms.
Asthma, which affects more than 22 million people in the U.S., can cause a patient’s airways to become inflamed and tighten, making it hard to breathe. Despite currently available treatments, many patients continue to experience asthma symptoms, which can have a negative impact on their ability to perform daily activities. One survey found 55 percent of people with asthma taking at least one treatment still experienced symptoms.

The approval of Spiriva Respimat establishes a new class of asthma medication known as long-acting muscarinic antagonists (LAMAs). Spiriva Respimat is steroid-free and works differently than a long-acting beta2 agonist (LABA). When asthma symptoms persist despite taking a daily maintenance treatment, adding Spiriva Respimat may help people breathe better and reduce attacks (also known as exacerbations).

“In my clinical experience, some patients with uncontrolled asthma, despite treatment, continue to experience symptoms, which can include coughing, wheezing, waking at night or shortness of breath,” said Dr. William Busse, Professor of Medicine, Division of Allergy, Pulmonary and Critical Care, at the University of Wisconsin School of Medicine and Public Health. “For patients who continue to experience these symptoms, Spiriva Respimat is a once-daily maintenance treatment that has been shown to provide additional bronchodilation to help patients breathe better and reduce asthma attacks.”

The FDA approved Spiriva Respimat based on efficacy and safety data from a comprehensive clinical trial program, including 12 trials of approximately 5,000 adults and adolescents with mild, moderate and severe symptomatic asthma on at least an inhaled corticosteroid (ICS). Data from this clinical program showed that the addition of Spiriva Respimat significantly improved lung function, as measured by forced expiratory volume in one second (FEV1 AUC0-3hr and trough FEV1) and reduced exacerbations for asthma patients, compared to placebo. An asthma exacerbation was defined as a progressive increase in asthma symptoms* or a decrease in a patient’s best morning peak expiratory flow (PEF) that required treatment with systemic steroids for at least three days.

The safety profile of Spiriva Respimat in asthma was demonstrated across the clinical trial program. The most common side effects (>2% incidence in the placebo-controlled trials with treatment durations between 12 and 52 weeks) were sore throat, sinus infections, bronchitis, and headache in adults.

Spiriva Respimat is now approved at two different doses. For asthma, the FDA approved a once-daily dose of 2.5 µg (delivered in 2 puffs of 1.25 µg each). Spiriva Respimat is also approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD) as a once-daily dose of 5 µg (delivered in 2 puffs of 2.5 µg each) for the maintenance treatment of COPD. Both doses for Spiriva Respimat should be taken as 2 puffs once daily.

Tiotropium, the active ingredient in Spiriva, has been used for more than 10 years as a maintenance treatment for COPD and has extensive clinical experience with over 40 million patient-years.

“For nearly a century, Boehringer Ingelheim has been dedicated to discovering medicines for serious respiratory diseases, such as asthma,” said Sabine Luik MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “As an industry leader in respiratory, it is our goal to develop new medicines that help address unmet needs. This FDA approval enhances asthma therapy by providing healthcare providers and patients with a new class of treatment to consider.”

*Shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms

About the Respimat Inhaler

The Respimat is the platform inhaler for the Boehringer Ingelheim respiratory 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).

About Spiriva Respimat in COPD

This FDA approval for asthma is the second indication for Spiriva Respimat, which is already approved for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema and to reduce exacerbations in COPD patients. Spiriva Respimat is not indicated for the relief of acute bronchospasm.

Indications

Spiriva Respimat, 2.5 µg, is a prescription medicine used once daily (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD) by relaxing your airways and keeping them open. COPD includes chronic bronchitis and emphysema. Spiriva Respimat also reduces the likelihood of COPD flare-ups (COPD exacerbations).

Spiriva Respimat, 1.25 µg, is a long-term, once-daily, prescription maintenance treatment of asthma for people 12 years and older.

Spiriva Respimat is not a treatment for sudden symptoms of asthma or COPD.

About Asthma

More than 22 million people in the U.S. have asthma. Asthma is a chronic disease and in the U.S., many patients taking currently available asthma treatments continue to experience symptoms. In a web-based survey of 1,812 asthma patients, 55 percent of patients taking asthma treatment still remained uncontrolled.

When a person with asthma comes into contact with an asthma trigger (e.g., infections, pollen, smoke), their airways can become inflamed, swollen and constricted and excess mucus is produced. These reactions can cause the airways to become narrower and irritated, making it difficult to breathe. People suffering from asthma experience recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Asthma attacks occur when symptoms become more intense or frequent.

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