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FDA Approves Stiolto Respimat

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

RIDGEFIELD, Conn., May 26, 2015 – 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

WARNING: ASTHMA‐RELATED DEATH

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.

Contraindication

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 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.

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and families. Our employees create and engage in programs that strengthen our communities. To learn more about how we make more health for more people, visit our Corporate Social Responsibility Report.

In 2014, Boehringer Ingelheim achieved net sales of about $16.96 billion dollars (13.3 billion euros). R&D expenditure corresponds to 19.9 percent of its net sales.

  1. Forced Expiratory Volume in 1 Second (FEV1)
  2. Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h)

Source: Boehringer Ingelheim Pharmaceuticals, Inc.

Posted: May 2015

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