Stiolto Respimat tiotropium bromide and olodaterol 3.124 ug; 2.736 ug Spray, Metered — NDC 0597-0155-28 (Billing 00597-0155-28)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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 to M 5 . In the airways, it exhibits pharmacological effects through inhibition of M 3 -receptors at the smooth muscle leading to bronchodilation.

The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

Olodaterol Olodaterol is a long-acting beta 2 -adrenergic agonist (LABA). The compound exerts its pharmacological effects by binding and activation of beta 2 -adrenoceptors after topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3', 5' adenosine monophosphate (cAMP).

Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells. In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta 2 -adrenoceptors compared to beta 1 -adrenoceptors and 2,299-fold greater agonist activity compared to beta 3 -adrenoceptors. The clinical significance of these findings is unknown.

Beta-adrenoceptors are divided into three subtypes: beta 1 -adrenoceptors predominantly expressed on cardiac muscle, beta 2 -adrenoceptors predominantly expressed on airway smooth muscle, and beta 3 -adrenoceptors predominantly expressed on adipose tissue. Beta 2 -agonists cause bronchodilation. Although the beta 2 -adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart.

The precise function of beta 2 -receptors in the heart is not known, but their presence raises the possibility that even highly selective beta 2 -agonists may have cardiac effects.

12.2Pharmacodynamics 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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 to M 5 . In the airways, it exhibits pharmacological effects through inhibition of M 3 -receptors at the smooth muscle leading to bronchodilation.

The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

Olodaterol Olodaterol is a long-acting beta 2 -adrenergic agonist (LABA). The compound exerts its pharmacological effects by binding and activation of beta 2 -adrenoceptors after topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3', 5' adenosine monophosphate (cAMP).

Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells. In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta 2 -adrenoceptors compared to beta 1 -adrenoceptors and 2,299-fold greater agonist activity compared to beta 3 -adrenoceptors. The clinical significance of these findings is unknown.

Beta-adrenoceptors are divided into three subtypes: beta 1 -adrenoceptors predominantly expressed on cardiac muscle, beta 2 -adrenoceptors predominantly expressed on airway smooth muscle, and beta 3 -adrenoceptors predominantly expressed on adipose tissue. Beta 2 -agonists cause bronchodilation. Although the beta 2 -adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart.

The precise function of beta 2 -receptors in the heart is not known, but their presence raises the possibility that even highly selective beta 2 -agonists may have cardiac effects.

12.3Pharmacokinetics 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 binding of [ 14 C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

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 experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.

In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4. 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 -receptors.

This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosy… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 30–60 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 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7) ms, and 8.5 (11.6) 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.

14 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 (1.25, 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 FEV 1 for the combination when compared to olodaterol alone.

The difference in trough FEV 1 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 FEV 1 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 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 less than 80% predicted normal [GOLD Stage 2-4]; post-bronchodilator FEV 1 to FVC ratio of less than 70%). All treatments were administered once daily in the morning.

The primary endpoints were change from baseline in FEV 1 AUC 0-3hr and trough FEV 1 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 FEV 1 was

1.37L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). Mean beta 2 -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 FEV 1 AUC 0-3hr and trough FEV 1 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 FEV 1 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. Table 2 FEV 1 AUC 0-3hr and Trough FEV 1 response for STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg after 24 weeks (primary endpoints; Trials 1 and 2) Trial 1 Trial 2 n Me… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility STIOLTO RESPIMAT No studies of the carcinogenicity, in vitro mutagenicity, or impairment of fertility were conducted with STIOLTO RESPIMAT, however, studies are available for the individual components, tiotropium and olodaterol. 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 basis, respectively. 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 , the mouse micronucleus assay in vivo , and the unscheduled DNA synthesis assay in primary rat hepatocytes 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 basis).

No such effects were observed at 9 mcg/kg/day (approximately 4 times than the RHDID on a mcg/m 2 basis). The fertility index; however, was not affected at inhalation doses up to 1,689 mg/kg/day (approximately 760 times the RHDID on a mcg/m 2 basis). 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 -adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis.

The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures. 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).