1.1 Maintenance Treatment of COPD

STIOLTO RESPIMAT is a combination of tiotropium and olodaterol indicated for long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

2.1 Recommended Dosage

The recommended dose of STIOLTO RESPIMAT is two inhalations once-daily at the same time of the day. Do not use STIOLTO RESPIMAT more than two inhalations every 24 hours.

2.2 Administration Information

For oral inhalation only.

Prior to first use, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [see Patient Counseling Information (17)].

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given STIOLTO RESPIMAT should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.10), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].

Inhalation Spray: STIOLTO RESPIMAT consists of a STIOLTO RESPIMAT inhaler and an aluminum cylinder (STIOLTO RESPIMAT cartridge) containing a combination of tiotropium bromide (as the monohydrate) and olodaterol (as the hydrochloride). The STIOLTO RESPIMAT cartridge is intended only for use with the STIOLTO RESPIMAT inhaler.

Each actuation from the STIOLTO RESPIMAT inhaler delivers 2.5 mcg tiotropium (equivalent to 3.124 mcg tiotropium bromide monohydrate) and 2.5 mcg olodaterol (equivalent to 2.736 mcg olodaterol hydrochloride) from the mouthpiece.

Two actuations equal one dose.

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

• 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 [see Contraindications (4)].
• Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.
• A 28-week, placebo-controlled US study comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of LABA, including olodaterol, one of the active ingredients in STIOLTO RESPIMAT.
• No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STIOLTO RESPIMAT has been conducted.
• Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes

STIOLTO RESPIMAT should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. STIOLTO RESPIMAT has not been studied in patients with acutely deteriorating COPD. The use of STIOLTO RESPIMAT in this setting is inappropriate.

STIOLTO RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STIOLTO RESPIMAT has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.

When beginning STIOLTO RESPIMAT, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing STIOLTO RESPIMAT, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If STIOLTO RESPIMAT no longer controls symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of STIOLTO RESPIMAT beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of STIOLTO RESPIMAT and Use With Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, STIOLTO 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.

5.4 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of STIOLTO RESPIMAT. If such a reaction occurs, therapy with STIOLTO RESPIMAT should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to STIOLTO RESPIMAT.

5.5 Paradoxical Bronchospasm

As with other inhaled medicines, STIOLTO RESPIMAT may cause paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, STIOLTO RESPIMAT should be stopped immediately and alternative therapy instituted.

5.6 Cardiovascular Effects

Olodaterol, like other beta2-agonists, 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 RESPIMAT may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Long acting beta2-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.

5.7 Coexisting Conditions

Olodaterol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

5.8 Worsening of Narrow-Angle Glaucoma

STIOLTO RESPIMAT should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.9 Worsening of Urinary Retention

STIOLTO RESPIMAT should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.10 Renal Impairment

Because tiotropium is a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with STIOLTO RESPIMAT should be monitored closely for anticholinergic side effects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

5.11 Hypokalemia and Hyperglycemia

Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.

In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment [see Drug Interactions (7.2)], which may increase the susceptibility for cardiac arrhythmias.

Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of olodaterol with the rates similar to those for placebo controls. Olodaterol has not been investigated in patients whose diabetes mellitus is not well controlled.

6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.

The clinical program for STIOLTO RESPIMAT included 7151 subjects with COPD in two 52-week active-controlled trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled cross-over trials, and four additional trials of shorter duration. A total of 1988 subjects received at least 1 dose of STIOLTO RESPIMAT. Adverse reactions observed in the ≤12-week trials were consistent with those observed in the 52-week trials, which formed the primary safety database.

The primary safety database consisted of pooled data from the two 52-week double-blind, active-controlled, parallel group confirmatory clinical trials (Trials 1 and 2). These trials included 5162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1029 were treated with STIOLTO RESPIMAT once daily. The STIOLTO RESPIMAT group was composed of mostly Caucasians (71.1%) with a mean age of 63.8 years and a mean percent predicted FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and olodaterol 5 mcg were included as active control arms and no placebo was used.

In these two clinical trials, 74% of patients exposed to STIOLTO RESPIMAT reported an adverse reaction compared to 76.6% and 73.3% in the olodaterol 5 mcg and tiotropium 5 mcg groups, respectively. The proportion of patients who discontinued due to an adverse reaction was 7.4% for STIOLTO RESPIMAT treated patients compared to 9.9% and 9.0% for olodaterol 5 mcg and tiotropium 5 mcg treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD.

The most common serious adverse reactions were COPD exacerbation and pneumonia.

Table 1 shows all adverse drug reactions that occurred with an incidence of >3% in the STIOLTO RESPIMAT treatment group and a higher incidence rate than the active comparator groups listed.

Other adverse drug reactions in patients receiving STIOLTO RESPIMAT that occurred in ≤3% of patients in clinical studies are listed below:

Metabolism and nutrition disorders: dehydration
Nervous system disorders: dizziness, insomnia
Eye disorders: glaucoma, intraocular pressure increased, vision blurred
Cardiac/vascular disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension
Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis
Gastrointestinal disorders: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including ileus paralytic
Skin and subcutaneous disorders: rash, pruritus, angioneurotic edema, urticaria, skin infection, and skin ulcer, dry skin, hypersensitivity (including immediate reactions)
Musculoskeletal and connective tissue disorders: arthralgia, joint swelling
Renal and urinary disorders: urinary retention, dysuria, and urinary tract infection

7.1 Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of olodaterol, one component of STIOLTO RESPIMAT, may be potentiated [see Warnings and Precautions (5.3, 5.6, 5.10, 5.11)].

7.2 Sympathomimetics, Xanthine Derivatives, Steroids, or Diuretics

Tiotropium has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids, without increases in adverse reactions. Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol [see Warnings and Precautions (5.11)].

7.3 Non-Potassium Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of STIOLTO RESPIMAT with non-potassium sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

STIOLTO RESPIMAT, as with other drugs containing beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.

7.5 Beta-Blockers

Beta-adrenergic receptor antagonists (beta-blockers) and the olodaterol component of STIOLTO RESPIMAT may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. 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, cardioselective beta-blockers could be considered, although they should be administered with caution.

7.6 Anticholinergics

There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.8, 5.9) and Adverse Reactions (6)].

7.7 Inhibitors of Cytochrome P450 and P-gp Efflux Transporter

In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol maximum plasma concentrations and AUC was observed [see Pharmacokinetics (12.3)]. Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment of STIOLTO RESPIMAT is necessary.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

COPD does not normally occur in children. The safety and effectiveness of STIOLTO RESPIMAT in the pediatric population has not been established.

8.5 Geriatric Use

Based on available data, no adjustment of STIOLTO RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

Of the 1029 patients who received STIOLTO RESPIMAT at the recommended dose once daily in the clinical studies from the pooled 1-year database, 525 (51.0%) were <65 years of age, 407 (39.6%) were 65 to <75, 96 (9.3%) were 75 to <85, and 1 (0.1%) was ≥85.

No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to the patient population overall.

8.6 Hepatic Impairment

No dose adjustment is needed in patients with mild and moderate hepatic impairment. A study in subjects with severe hepatic impairment was not performed [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is required for patients with renal impairment. However, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with STIOLTO RESPIMAT should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.10), and Clinical Pharmacology (12.3)].

Tiotropium

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, were observed following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.

Olodaterol

The expected signs and symptoms with overdosage of olodaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of olodaterol.

Treatment of overdosage consists of discontinuation of STIOLTO RESPIMAT together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of STIOLTO RESPIMAT. Cardiac monitoring is recommended in cases of overdosage.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dose-Ranging Trials

Dose selection for STIOLTO RESPIMAT was primarily based on trials for the individual components, tiotropium bromide and olodaterol.

Dose selection was also supported by two randomized, double-blind, active-controlled, 4-week trials. In one trial in 232 patients with COPD, three tiotropium doses (1.25, 2.5, and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy. Results demonstrated improvement in trough FEV1 for the combination when compared to olodaterol alone. The difference in trough FEV1 for the tiotropium bromide/olodaterol doses of 1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively. In the second trial in 360 patients with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to tiotropium monotherapy. The difference in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L (95% CI -0.029, 0.076), 0.033 L (-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively. Results of these trials supported the evaluation of once-daily doses of tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.

Confirmatory Trials

A total of 5162 COPD patients (1029 receiving STIOLTO RESPIMAT, 1038 receiving olodaterol 5 mcg, and 1033 receiving tiotropium bromide 5 mcg) were studied in two confirmatory trials of STIOLTO RESPIMAT. Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials that compared STIOLTO RESPIMAT to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products were administered via the RESPIMAT inhaler.

The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal [GOLD Stage 2-4]; post-bronchodilator FEV1 to FVC ratio of less than 70%). All treatments were administered once daily in the morning. The primary endpoints were change from baseline in FEV1 AUC0-3hr and trough FEV1 after 24 weeks of treatment.

The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV1 was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). Mean beta2-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [47%] and xanthines [10%].

In both Trials 1 and 2, STIOLTO RESPIMAT demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg (Table 2). The increased bronchodilator effects of STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period. STIOLTO RESPIMAT displayed a mean increase in FEV1 from baseline of 0.137 L (range: 0.133-0.140 L) within 5 minutes after the first dose. Patients treated with STIOLTO RESPIMAT used less rescue medication compared to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.

For the subset of patients (n=521) who completed extended lung function measurements up to 12 hours post-dose, STIOLTO RESPIMAT showed a significantly greater FEV1 response compared to tiotropium 5 mcg and olodaterol 5 mcg over the full 24-hour dosing interval. Results from Trial 2 are shown in Figure 1.

Figure 1 FEV1 profile for STIOLTO RESPIMAT, tiotropium 5 mcg and olodaterol 5 mcg over a 24-hour dosing interval after 24 weeks (12 hr PFT subset from Trial 2)

The St. George's Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2 and in two additional 12-week placebo-controlled trials (Trials 3 and 4).

In the first 12-week trial, SGRQ responder rates at week 12 (defined as an improvement in score of 4 or more as a threshold) were 53%, 42%, and 31% for STIOLTO RESPIMAT, tiotropium 5 mcg, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1, 2.4) and 2.5 (95% CI 1.6, 3.8) for STIOLTO RESPIMAT vs. tiotropium 5 mcg and STIOLTO RESPIMAT vs. placebo, respectively. In the second 12-week trial, results were similar with odds ratios of 1.5 (95% CI 1.0, 2.3) and 2.2 (95% CI 1.5, 3.4) for STIOLTO RESPIMAT vs. tiotropium 5 mcg and STIOLTO RESPIMAT vs. placebo, respectively. For the 52-week trials similar responder rates were seen. In Trial 1, the odds ratios for STIOLTO vs. tiotropium 5 mcg and STIOLTO vs. olodaterol 5 mcg at week 24 were 1.6 (95% CI 1.2, 2.0) and 1.9 (95% CI 1.5, 2.4), respectively. The results were similar in the 52-week Trial 2, with odds ratios for STIOLTO vs. tiotropium 5 mcg and STIOLTO vs. olodaterol 5 mcg of 1.3 (95% CI 1.0, 1.7) and 1.5 (95% CI 1.1, 1.9), respectively.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.

Serious Asthma-Related Events

Inform patients that LABA, such as STIOLTO RESPIMAT, when used as monotherapy [without an inhaled corticosteroid], increase the risk of serious asthma-related events, including asthma-related death. STIOLTO RESPIMAT is not indicated for the treatment of asthma.

Not for Acute Symptoms

STIOLTO RESPIMAT is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)

Instruct patients to notify their physician immediately if they experience any of the following:

• Worsening of symptoms
• Decreasing effectiveness of inhaled, short-acting beta2-agonists
• Need for more inhalations than usual of inhaled, short-acting beta2-agonists
• Significant decrease in lung function as outlined by the physician

Instruct patients not to stop therapy with STIOLTO RESPIMAT without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

When patients are prescribed STIOLTO RESPIMAT, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once-daily dose of STIOLTO RESPIMAT. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

Risks Associated with Beta2-Agonist Therapy

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Immediate Hypersensitivity Reactions

Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of STIOLTO RESPIMAT. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.

Paradoxical Bronchospasm

Inform patients that STIOLTO RESPIMAT can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue STIOLTO RESPIMAT.

Urinary Retention

Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.

Visual Effects

Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eye drops alone are not considered to be effective treatment.

Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.

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

Instructions for Administering STIOLTO RESPIMAT

It is important for patients to understand how to correctly administer STIOLTO RESPIMAT inhalation spray using the STIOLTO RESPIMAT inhaler. Instruct patients that STIOLTO RESPIMAT inhalation spray should only be administered via the STIOLTO RESPIMAT inhaler and the STIOLTO RESPIMAT inhaler should not be used for administering other medications.

Instruct patients that priming STIOLTO RESPIMAT is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed. STIOLTO RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.