FDA Approves Boehringer Ingelheim's STIOLTO RESPIMAT Inhalation Spray as Once-Daily Maintenance Treatment for COPD

STIOLTO RESPIMAT is the only COPD treatment that includes two proven agents: tiotropium, the active ingredient in SPIRIVA®, and olodaterol

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Boehringer Ingelheim Pharmaceuticals, Inc.

May 26, 2015, 08:00 ET

RIDGEFIELD, Conn., May 26, 2015 /PRNewswire/ -- 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 FEV₁ⁱ and FEV₁AUC_0-3hⁱⁱ.

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 AUC_0-3h) at 24 weeks versus tiotropium and olodaterol alone. These 52-week Phase III TONADO™ 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.

Please see complete Important Safety Information below.

"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).

For more information about STIOLTO RESPIMAT, please visit www.STIOLTO.com.

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.

Please click for full Prescribing Information for STIOLTO RESPIMAT.

About Spiriva^® HandiHaler^® (tiotropium bromide inhalation powder) and SPIRIVA^®RESPIMAT^® (tiotropium bromide) Inhalation Spray

INDICATION
SPIRIVA HandiHaler and SPIRIVA RESPIMAT are indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, and for reducing COPD exacerbations.

IMPORTANT SAFETY INFORMATION
SPIRIVA is contraindicated in patients with a history of hypersensitivity to tiotropium, ipratropium (atropine derivatives), or any component of either product.

SPIRIVA is not indicated for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy.

Immediate hypersensitivity reactions, including urticaria, angioedema (swelling of lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of SPIRIVA. Additionally, inhaled medicines, including SPIRIVA, may cause paradoxical bronchospasm. If any of these occurs, treatment with SPIRIVA should be stopped and other treatments considered.

Patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA.

SPIRIVA HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins.

SPIRIVA should be used with caution in patients with narrow-angle glaucoma or urinary retention. Prescribers should instruct patients to consult a physician immediately should any signs or symptoms of narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction occur.

Since dizziness and blurred vision may occur with the use of SPIRIVA, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

Patients with moderate to severe renal impairment (creatinine clearance of </= 50 mL/min for SPIRIVA HandiHaler) and (creatinine clearance of </= 60 mL/min for SPIRIVA RESPIMAT) and treated with SPIRIVA should be monitored closely for anticholinergic side effects.

SPIRIVA may interact additively with concomitantly used anticholinergic medications. Avoid coadministration with other anticholinergic containing drugs.

The most common adverse reactions >5% incidence and exceeded placebo by >1% with SPIRIVA HandiHaler (placebo) were upper respiratory tract infection 41% (37%), dry mouth 16% (3%), sinusitis 11% (9%), pharyngitis 9% (7%), non-specific chest pain 7% (5%), urinary tract infection 7% (5%), dyspepsia 6% (5%), and rhinitis 6% (5%). In addition, the most common reported adverse reaction >3% incidence and higher than placebo from the 4-year trial with SPIRIVA HandiHaler (placebo) not included above were headache 5.7% (4.5%), depression 4.4% (3.3%), insomnia 4.4% (3.0%), and arthralgia 4.2% (3.1%).

The most common adverse reactions >3% incidence and higher than placebo with SPIRIVA RESPIMAT (placebo) were pharyngitis 11.5% (10.1%), cough 5.8% (5.5%), dry mouth 4.1% (1.6%), and sinusitis 3.1% (2.7%).

SPIRIVA capsules should not be swallowed and should only be inhaled through the mouth (oral inhalation) using the HandiHaler device and the HandiHaler device should not be used for administering other medications.

Inform patients not to spray SPIRIVA RESPIMAT into the eyes as this may cause blurring of vision and pupil dilation.

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.

For full prescribing information, please visit www.SPIRIVA.com, or call 1-800-542-6257 option #4.

Please click for full Prescribing Information for SPIRIVA HandiHaler and for SPIRIVA RESPIMAT.

About Striverdi^® Respimat^® (olodaterol) Inhalation Spray

Indication
Striverdi^® Respimat^® (olodaterol) Inhalation Spray is a long-acting beta₂-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations: STRIVERDI RESPIMAT is not indicated to treat acute deteriorations of COPD and is not indicated to treat asthma.

Important Safety Information for STRIVERDI RESPIMAT

WARNING: ASTHMA-RELATED DEATH
Long-acting beta₂-adrenergic agonists (LABA) 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) or 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 LABA, including olodaterol, the active ingredient in STRIVERDI RESPIMAT. The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI 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.

STRIVERDI RESPIMAT should not be initiated in patients with acutely deteriorating COPD, which may be a life threatening condition, or used as rescue therapy for acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting beta₂ agonist.

STRIVERDI RESPIMAT should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂ agonists as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

STRIVERDI RESPIMAT may produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, STRIVERDI RESPIMAT should be discontinued immediately and alternative therapy instituted.

STRIVERDI RESPIMAT can produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms, and should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension. If cardiovascular symptoms occur, STRIVERDI RESPIMAT may need to be discontinued.

STRIVERDI RESPIMAT should be used with 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. Be alert to hypokalemia and hyperglycemia.

Immediate hypersensitivity reactions, including angioedema, may occur. If such a reaction occurs, therapy with STRIVERDI RESPIMAT should be stopped at once and alternative treatment should be considered.

The most commonly reported adverse reactions (≥2% incidence and more than placebo) with STRIVERDI RESPIMAT (and placebo) were nasopharyngitis, 11.3% (7.7%); upper respiratory tract infection, 8.2% (7.5%); bronchitis, 4.7% (3.6%); urinary tract infection, 2.5% (1.0%); cough, 4.2% (4.0%); dizziness, 2.3% (2.1%); rash, 2.2% (1.1%); diarrhea, 2.9% (2.5%); back pain, 3.5% (2.7%); and arthralgia 2.1% (0.8%).

STRIVERDI RESPIMAT should be used with extreme caution in patients treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated.

STRIVERDI RESPIMAT should be used with caution in patients treated with additional adrenergic drugs, non-potassium-sparing diuretics, and beta-blockers.

STRIVERDI RESPIMAT is for oral inhalation only.

Please see full Prescribing Information, including boxed WARNING, Medication Guide, and Instructions for Use for STRIVERDI RESPIMAT.

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.

For more information please visit www.us.boehringer-ingelheim.com, or follow us on Twitter @BoehringerUS.

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

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.