Stiolto Respimat

1 INDICATIONS AND USAGE STIOLTO RESPIMAT is a combination of tiotropium bromide, an anticholinergic and olodaterol, a long-acting beta 2 -adrenergic agonist (LABA) indicated for the long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1.1 ) Important limitations: STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of COPD. ( 1.1 ) STIOLTO RESPIMAT is NOT indicated to treat asthma. ( 1.1 ) 1.1 Maintenance Treatment of COPD STIOLTO RESPIMAT is a combination of tiotropium bromide and olodaterol indicated for long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Important Limitations of Use STIOLTO RESPIMAT is not indicated to treat acute deteriorations of COPD [see Warnings and Precautions (5.2) ]. STIOLTO RESPIMAT is not indicated to treat asthma. The safety and effectiveness of STIOLTO RESPIMAT in asthma have not been established.

2 DOSAGE AND ADMINISTRATION For oral inhalation only. Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day. ( 2 ) 2.1 Recommended Dosage The recommended dosage 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) ] .

5 WARNINGS AND PRECAUTIONS LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate STIOLTO RESPIMAT in acutely deteriorating COPD patients. ( 5.2 ) Do not use for relief of acute symptoms. Concomitant short-acting beta 2 -agonists can be used as needed for acute relief. ( 5.2 ) Do not exceed the recommended dosage. Excessive use of STIOLTO RESPIMAT, or use in conjunction with other medications containing LABA can result in clinically significant cardiovascular effects and may be fatal. ( 5.3 ) Immediate hypersensitivity reactions: Discontinue STIOLTO RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. ( 5.4 ) Life-threatening paradoxical bronchospasm can occur. Discontinue STIOLTO RESPIMAT immediately. ( 5.5 ) Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or sensitivity to sympathomimetic drugs. ( 5.6 , 5.7 ) Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. ( 5.8 ) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. ( 5.9 ) Be alert to hypokalemia and hyperglycemia. ( 5.11 ) 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 beta 2 -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 beta 2 -agonist. When beginning STIOLTO RESPIMAT, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructe…

4 CONTRAINDICATIONS Use of a LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1) ] . STIOLTO RESPIMAT is not indicated for the treatment of asthma. STIOLTO RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product [see Warnings and Precautions (5.4) ] . 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 RESPIMAT. Use of a LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 4 ) Hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product. ( 4 )

7 DRUG INTERACTIONS Other adrenergic drugs may potentiate effect. Use with caution. ( 5.3 , 7.1 ) Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. ( 7.2 , 7.3 ) MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate effect on cardiovascular system. Use with extreme caution. ( 7.4 ) Beta-blockers may decrease effectiveness. Use with caution and only when medically necessary. ( 7.5 ) Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs. ( 7.6 ) 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 dosage 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 beta 2 -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 dosage. No dosage adjustment of STIOLTO RESPIMAT is necessary.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled clinical studies with STIOLTO RESPIMAT or its individual components, tiotropium bromide and olodaterol, in pregnant women to inform of drug-associated risk of adverse pregnancy-related outcomes. Animal reproduction studies were conducted with the individual components of STIOLTO RESPIMAT, tiotropium bromide and olodaterol. There are clinical considerations with the use of STIOLTO RESPIMAT in pregnant women (see Clinical Considerations ) . STIOLTO RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss was observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively (see Data ) . Based on animal studies, olodaterol was not teratogenic when administered to pregnant rats or rabbits during organogenesis at inhalation doses of approximately 2,731 or 1,353 times the MRHDID (on an AUC basis), in rats or rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor and Delivery There are no adequate and well-controlled human studies that have investigated the effects of STIOLTO RESPIMAT on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of STIOLTO RESPIMAT during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Data Animal Data Animal reproduction studies with the combination of tiotropium and olodaterol are not available; however, studies are available with the individual components. Tiotropium In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and 8 times the MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m 2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m 2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively). Olodaterol Olodaterol was not teratogenic in rats at inhalation doses approximately 2,731 times the MRHDID (on an AUC basis at a maternal inhalation dose of 1,054 mcg/kg/day). No significant effects occurred in rabbits at inhalation doses approximately 1,353 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 974 mcg/kg/day). Placental transfer of olodaterol was observed in pregnant rats. Olodaterol has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 2,489 mcg/kg/…

6 ADVERSE REACTIONS LABA, such as olodaterol, one of the active components in STIOLTO RESPIMAT, as monotherapy (without an inhaled corticosteroid) for asthma, increase the risk of asthma-related events. STIOLTO RESPIMAT is not indicated for the treatment of asthma [see Warning and Precautions (5.1) ]. The following adverse reactions are described, or described in greater detail, in other sections: Immediate hypersensitivity reactions [see Warnings and Precautions (5.4) ] Paradoxical bronchospasm [see Warnings and Precautions (5.5) ] Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.8) ] Worsening of urinary retention [see Warnings and Precautions (5.9) ] The most common adverse reactions (>3% incidence and more than an active control) were nasopharyngitis, cough, and back pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 7,151 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 1,988 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 5,162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1,029 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 FEV 1 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. Table 1 Number and frequency of adverse drug reactions greater than 3% (and higher than any of the comparators tiotropium and/or olodaterol) in COPD patients exposed to STIOLTO RESPIMAT: Pooled data from the two 52-week, double-blind, active-controlled clinical trials in COPD patients 40 years of age and older Treatment STIOLTO RESPIMAT (once daily) Tiotropium (5 mcg once daily) Olodaterol (5 mcg once daily) Body system (adverse drug reaction) n=1,029 n (%) n=1,033 n (%) n=1,038 n (%) Infections and infestations Nasopharyngitis 128 (12.4) 121 (11.7) 131 (12.6) Respiratory, thoracic, and mediastinal disorders Cough 40 (3.9) 45 (4.4) 31 (3.0) Musculoskeletal and connective tissue disorders Back Pain 37 (3.6) 19 (1.8) 35 (3.4) Other adverse drug reactions in patients receiving STIOLTO RESPIMAT that occ…