STIOLTO RESPIMAT- tiotropium bromide and olodaterol_spray, metered

STIOLTO RESPIMAT STIOLTO RESPIMAT contains both tiotropium and olodaterol. The properties described below for the individual components apply to STIOLTO RESPIMAT. These drugs represent 2 different classes of medication (an anticholinergic and a beta-agonist) that have different effects on clinical and physiological indices. Tiotropium Tiotropium is a long-acting, muscarinic antagonist which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M 1 5 3 in vitro in vivo Olodaterol Olodaterol is a long-acting beta 2 2 In vitro 2 1 3 Beta-adrenoceptors are divided into three subtypes: beta 1 2 3 2 2 2 2 Cardiac Electrophysiology STIOLTO RESPIMAT In two 52-week randomized, double-blind trials using STIOLTO RESPIMAT that enrolled 5,162 patients with COPD, ECG assessments were performed post-dose on days 1, 85, 169, and 365. In a pooled analysis the number of subjects with changes from baseline-corrected QT interval of >30 msec using both the Bazett (QTcB) and Fredericia (QTcF), corrections of QT for heart rate were not different for the STIOLTO RESPIMAT group compared to olodaterol 5 mcg and tiotropium 5 mcg across the assessments conducted. Tiotropium The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium inhalation powder 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3. 2 msec and 0. 8 msec for tiotropium inhalation powder 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of >=60 msec. In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30en dash60 msec was higher in the tiotropium group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical trials with tiotropium did not detect an effect of the drug on QTc intervals. Olodaterol The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomized, placebo- and active (moxifloxacin)- controlled study at single doses of 10, 20, 30, and 50 mcg. Dose-dependent QtcI (individual subject corrected QT interval) prolongation was observed. The maximum mean (one-sided 95% upper confidence bound) difference in QTcI from placebo after baseline correction was 2. 7) ms, and 8. 6) ms following doses of 10, 20, 30, and 50 mcg, respectively. The effect of 5 mcg and 10 mcg olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 mcg, 10 mcg, and placebo. STIOLTO RESPIMAT When STIOLTO RESPIMAT was administered by the inhalation route, the pharmacokinetic parameters for tiotropium and for olodaterol were similar to those observed when each active substance was administered separately. Tiotropium Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. Olodaterol Olodaterol showed linear pharmacokinetics. On repeated once-daily inhalation, steady-state of olodaterol plasma concentrations was achieved after 8 days, and the extent of exposure was increased up to 1. 8-fold as compared to a single dose. Absorption Tiotropium Following inhalation of the solution by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium for the same reason. Maximum tiotropium plasma concentrations were observed 5 to 7 minutes after inhalation. Olodaterol Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure. Distribution Tiotropium The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier. Olodaterol Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1,110 L), suggesting extensive distribution into tissue. In vitro 14 Elimination Metabolism Tiotropium The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors. In vitro In vitro Olodaterol Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta 2 Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides. Excretion Tiotropium The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of the solution by patients with COPD, urinary excretion is 18. 932 mcg) of the dose, the remainder being mainly non-absorbed drug in the gut that is eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter. Olodaterol Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. However, the effective half-life at daily dose of 5 mcg calculated from C max Following intravenous administration of [ 14 Drug Interactions STIOLTO RESPIMAT Pharmacokinetic drug interaction studies with STIOLTO RESPIMAT have not been performed; however, such studies have been conducted with individual components tiotropium and olodaterol. When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately. Tiotropium An interaction study with tiotropium (14. 4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once-daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC 0-4h max Common concomitant medications (long-acting beta 2 Olodaterol Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP 2C9 and ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9) inhibitor. Fluconazole Ketoconazole max 0-1 Tiotropium Specific Populations Olodaterol A pharmacokinetic meta-analysis showed that no dose adjustment is necessary based on the effect of age, gender, and weight on systemic exposure in COPD patients after inhalation of olodaterol. Geriatric Patients Tiotropium: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (347 mL/min in COPD patients <65 years to 275 mL/min in COPD patients >=65 years). This did not result in a corresponding increase in AUC 0-6,ss max,ss Renal Impairment Tiotropium Following inhaled administration of therapeutic doses of tiotropium to steady-state to patients with COPD, mild renal impairment (creatinine clearance 60 - <90 mL/min) resulted in 23% higher AUC 0-6,ss max,ss 0-6,ss max,ss 0-4 max Olodaterol Olodaterol levels were increased by approximately 40% in subjects with severe renal impairment. A study in subjects with mild and moderate renal impairment was not performed. Hepatic Impairment Tiotropium The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. Olodaterol Subjects with mild and moderate hepatic impairment showed no changes in C max.

STIOLTO RESPIMAT is a combination of tiotropium bromide, an anticholinergic and olodaterol, a long-acting beta 2 1. 1 Important limitations: STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of COPD. 1 STIOLTO RESPIMAT is NOT indicated to treat asthma. 1 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.

For oral inhalation only. Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day. ( 2 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. 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. 7) Clinical Pharmacology (12.

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. gov/medwatch 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 In these two clinical trials, 74% of patients exposed to STIOLTO RESPIMAT reported an adverse reaction compared to 76. 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. 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 Tiotropium Olodaterol Body system (adverse drug reaction) n=1,029 n=1,033 n=1,038 Infections and infestations Nasopharyngitis 128 (12. 6) Respiratory, thoracic, and mediastinal disorders Cough 40 (3. 0) Musculoskeletal and connective tissue disorders Back Pain 37 (3. 4) 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: Nervous system disorders: Eye disorders: Cardiac/vascular disorders: Respiratory, thoracic, and mediastinal disorders: Gastrointestinal disorders: Skin and subcutaneous disorders: Musculoskeletal and connective tissue disorders: Renal and urinary disorders: COPD Exacerbation Reduction Trial In a one year trial (Trial 5) of 7,880 patients to compare rates of COPD exacerbations, 3,939 patients were treated with STIOLTO RESPIMAT and 3,941 patients were treated with tiotropium 5 mcg inhalation spray. The safety profile of STIOLTO RESPIMAT was similar to that of tiotropium 5 mcg inhalation spray and consistent with that documented in the STIOLTO RESPIMAT primary safety database.

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 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.

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects. 7 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 (see Data (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. 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 2 2 2 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/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. Risk Summary There are no data on the presence of tiotropium or olodaterol in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium, olodaterol, and/or their metabolites are present in the milk of lactating rats, however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear (see Data Data The distributions of tiotropium bromide or olodaterol into milk were investigated in separate studies after a single intravenous administration of 10 mg/kg or 0. 4 mumol/kg, respectively, to lactating rats. Tiotropium, olodaterol, and/or their metabolites are present in the milk of lactating rats at concentrations above those in plasma. COPD does not normally occur in children. The safety and effectiveness of STIOLTO RESPIMAT in the pediatric population has not been established. Based on available data, no adjustment of STIOLTO RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12. 3) Of the 1,029 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. 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) 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) Clinical Pharmacology (12.

Other adrenergic drugs may potentiate effect. Use with caution. 1 Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. 3 MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate effect on cardiovascular system. Use with extreme caution. 4 Beta-blockers may decrease effectiveness. Use with caution and only when medically necessary. 5 Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs. 6 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. 11) 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) 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. STIOLTO RESPIMAT, as with other drugs containing beta 2 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. , 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. 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. 9) Adverse Reactions (6) 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.

OVERDOSAGE
STIOLTO RESPIMAT contains both tiotropium bromide and olodaterol; therefore, the risks associated with overdosage for the individual components described below apply to STIOLTO RESPIMAT. 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. , 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.
NONCLINICAL TOXICOLOGY
STIOLTO RESPIMAT No studies of the carcinogenicity, in vitro Tiotropium No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0. 5 times the recommended human daily inhalation dose (RHDID) on a mcg/m 2 Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assay in human lymphocytes in vitro in vivo in vitro In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 35 times the RHDID on a mcg/m 2 2 2 Olodaterol Two-year inhalation studies were conducted in rats and mice to assess the carcinogenic potential of olodaterol. Lifetime treatment of female rats induced leiomyomas of the mesovarium at doses of 25. 8 and 270 mcg/kg/day (approximately 18- and 198-fold, respectively, the RHDID on an AUC basis). No tumor findings were observed in male rats at doses up to 270 mcg/kg/day (approximately 230-fold the RHDID on an AUC basis). Lifetime treatment of female mice induced leiomyomas and leiomyosarcomas of the uterus at doses >=76. 9 mcg/kg/day (approximately 106-fold the RHDID on an AUC basis). No tumor findings were observed in male mice at doses up to 255 mcg/kg/day (approximately 455-fold the RHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas of the female rodent reproductive tract have been similarly demonstrated with other beta 2 Olodaterol was not mutagenic in the in vitro in vitro Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3,068 mcg/kg/day (approximately 2,322 times the RHDID on an AUC basis).
CLINICAL STUDIES
The safety and efficacy of STIOLTO RESPIMAT were evaluated in a clinical development program that included three dose ranging trials, two active-controlled trials, three active- and placebo-controlled trials, and one placebo-controlled trial. The efficacy of STIOLTO RESPIMAT is based primarily on two 4-week dose-ranging trials in 592 COPD patients and two confirmatory active-controlled 52-week trials (Trials 1 and 2) in 5,162 COPD patients. 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. 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 FEV 1 1 1 Confirmatory Trials A total of 5,162 COPD patients (1,029 receiving STIOLTO RESPIMAT, 1,038 receiving olodaterol 5 mcg, and 1,033 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 FEV 1 1 1 0-3hr 1 The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64. Mean post-bronchodilator FEV 1 2 In both Trials 1 and 2, STIOLTO RESPIMAT demonstrated significant improvements in FEV 1 0-3hr 1 1 Table 2 FEV 1 0-3hr 1 Trial 1 Trial 2 n Mean (L) Difference (L) n Mean (L) Difference (L) Pre-treatment baseline FEV 1 p<=0. 0001 for all comparisons between STIOLTO RESPIMAT and the monotherapies. FEV 1 0-3hr STIOLTO RESPIMAT 522 0. 256 - 502 0. 268 - Tiotropium 5 mcg 526 0. 103 Olodaterol 5 mcg 525 0. 132 Trough FEV 1 STIOLTO RESPIMAT 521 0. 136 - 497 0. 145 - Tiotropium 5 mcg 520 0. 050 Olodaterol 5 mcg 519 0. 088 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 FEV 1 Figure 1 FEV 1 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. 5 (95% CI 1. 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. 2 (95% CI 1. 4) for STIOLTO RESPIMAT vs. 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. 9 (95% CI 1. 4), respectively. The results were similar in the 52-week Trial 2, with odds ratios for STIOLTO vs. olodaterol 5 mcg of 1. 3 (95% CI 1. 9), respectively. Exacerbations Tiotropium 5 mcg Trials Evaluating Exacerbations The effect of tiotropium 5 mcg inhalation spray on exacerbations was evaluated in three 48-week randomized, double-blind, placebo-controlled clinical trials that included COPD exacerbations as the primary endpoint. Exacerbations of COPD were defined as a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD, with duration of three days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalization. In a pooled analysis of the first two trials, tiotropium 5 mcg significantly reduced the number of COPD exacerbations compared to placebo with a rate ratio of 0. 78 (95% CI 0. In the third trial, tiotropium 5 mcg delayed the time to first COPD exacerbation compared to placebo with a hazard ratio of 0. 69 (95% CI 0. STIOLTO RESPIMAT Trial Evaluating Exacerbations In a one-year, randomized, double-blind, active-controlled parallel group clinical trial (Trial 5), the effect of STIOLTO RESPIMAT on COPD exacerbations was compared with tiotropium 5 mcg inhalation spray. Exacerbations were defined as above. Enrolled patients (3,939 patients receiving STIOLTO RESPIMAT and 3,941 patients receiving tiotropium 5 mcg inhalation spray) had a history of COPD exacerbation in the previous 12 months. The primary endpoint was the annualized rate of moderate to severe COPD exacerbations. The majority of patients were male (71%) and Caucasian (79%). The mean age was 66 years, and mean post-bronchodilator FEV 1 Figure 1.

Boehringer Ingelheim Pharmaceuticals Inc.

STIOLTO RESPIMAT- tiotropium bromide and olodaterol_spray, metered Product manual source documgent