1.1 Maintenance Treatment of COPD

STRIVERDI RESPIMAT is a long-acting beta2-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

1.2 Important Limitations of Use

STRIVERDI RESPIMAT is not indicated to treat acute deteriorations of COPD [see Warnings and Precautions (5.2)].

STRIVERDI RESPIMAT is not indicated to treat asthma. The safety and effectiveness of STRIVERDI RESPIMAT in asthma have not been established.

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

• The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI RESPIMAT is not indicated for the treatment of asthma [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 STRIVERDI RESPIMAT.
• No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STRIVERDI 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

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

STRIVERDI RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STRIVERDI 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 STRIVERDI 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 STRIVERDI 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 STRIVERDI 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 STRIVERDI RESPIMAT beyond the recommended dosage is not appropriate in this situation.

5.3 Excessive Use of STRIVERDI RESPIMAT and Use with Long-Acting Beta2-Agonists

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

5.4 Paradoxical Bronchospasm

As with other inhaled beta2-agonists, STRIVERDI RESPIMAT may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, STRIVERDI RESPIMAT should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

STRIVERDI RESPIMAT, 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, STRIVERDI 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.

5.6 Co-existing Conditions

STRIVERDI RESPIMAT, 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.

5.7 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 STRIVERDI RESPIMAT with the rates similar to those for placebo controls. STRIVERDI RESPIMAT has not been investigated in patients whose diabetes mellitus is not well controlled.

5.8 Hypersensitivity Reactions

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

6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

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

The STRIVERDI RESPIMAT clinical development program included seven dose-ranging trials and eight confirmatory trials. Four of the confirmatory trials were 6-week cross-over trials and four were 48-week parallel group trials. Adverse reactions observed in the dose-ranging trials and four 6-week cross-over trials were consistent with those observed in the 48-week parallel group trials, which formed the primary safety database.

The primary safety database consisted of pooled data from the four 48-week double-blind, active and placebo-controlled, parallel group confirmatory clinical trials. These trials included 3,104 adult COPD patients (77% males and 23% females) 40 years of age and older. Of these patients, 876 and 883 patients were treated with STRIVERDI RESPIMAT 5 mcg and 10 mcg once-daily, respectively. The STRIVERDI RESPIMAT groups were composed of mostly Caucasians (66%) with a mean age of 64 years and a mean percent predicted FEV1 at baseline of 44% for both the 5 mcg and 10 mcg treatment groups. Control arms for comparison included placebo in all four trials plus formoterol 12 mcg in two trials.

In these four clinical trials, seventy-two percent (72%) of patients exposed to any dose of STRIVERDI RESPIMAT reported an adverse reaction compared to 71% in the placebo group. The proportion of patients who discontinued due to an adverse reaction was 7.2% for STRIVERDI RESPIMAT treated patients compared to 8.8% for placebo treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD. The most common serious adverse reactions were COPD exacerbation, pneumonia, and atrial fibrillation.

Table 1 shows all adverse drug reactions reported by at least 2% of patients (and higher than placebo) who received STRIVERDI RESPIMAT 5 mcg during the 48-week trials.

Additional adverse reactions that occurred in greater than 2% (and higher than placebo) of patients exposed to STRIVERDI RESPIMAT 10 mcg were pneumonia, constipation, and pyrexia.

Lung cancers were reported in 6 (0.7%), 3 (0.3%), and 2 (0.2%) patients who received STRIVERDI RESPIMAT 10 mcg, 5 mcg, and placebo, respectively.

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 STRIVERDI RESPIMAT may be potentiated [see Warnings and Precautions (5.3, 5.5, 5.6, 5.7)].

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of STRIVERDI RESPIMAT [see Warnings and Precautions (5.7)].

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 beta-agonists with non-potassium-sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

STRIVERDI RESPIMAT, as with other 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 STRIVERDI 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 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 maximum plasma concentrations and AUC was observed [see Clinical Pharmacology (12.3)]. STRIVERDI RESPIMAT was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dosage. No dosage adjustment is necessary.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

STRIVERDI RESPIMAT is not indicated for use in children. The safety and effectiveness of STRIVERDI RESPIMAT in the pediatric population have not been established.

8.5 Geriatric Use

Based on available data, no adjustment of STRIVERDI RESPIMAT dosage in geriatric patients is necessary.

Of the 876 patients who received STRIVERDI RESPIMAT at the recommended dose of 5 mcg once-daily in the clinical studies from the pooled 1-year database, 485 were less than or equal to 65 years of age and 391 (44.6%) were greater than 65 years of age.

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

Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.

8.7 Renal Impairment

Subjects with severe renal impairment showed no clinically relevant changes in Cmax or AUC compared to their healthy controls.

12.1 Mechanism of Action

Olodaterol is a long-acting beta2-adrenergic agonist (LABA). The compound exerts its pharmacological effects by binding and activation of beta2-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 beta2-adrenoceptors compared to beta1-adrenoceptors and 2,299-fold greater agonist activity compared to beta3-adrenoceptors. The clinical significance of these findings is unknown.

Beta-adrenoceptors are divided into three subtypes: beta1-adrenoceptors predominantly expressed on cardiac smooth muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle, and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation. Although the beta2-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 beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-agonists may have cardiac effects.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 MRHDID on an AUC basis). No tumor findings were observed in male rats at doses up to 270 mcg/kg/day (approximately 230-fold the MRHDID 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 MRHDID on an AUC basis). No tumor findings were observed in male mice at doses up to 255 mcg/kg/day (approximately 455-fold the MRHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas of the female rodent reproductive tract have been similarly demonstrated with other β2-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 MRHDID on an AUC basis).

Dose-ranging trials

The first COPD dose-ranging trial was a randomized, double-blind, placebo-controlled, single-dose, 5-way cross-over trial in 36 patients. Results demonstrated dose-related improvements in forced expiratory volume in one second (FEV1) compared to placebo. The difference in trough FEV1 from placebo for the 2, 5, 10, and 20 mcg doses were 0.07L (95% CI 0.03, 0.11), 0.10L (0.06, 0.14), 0.11L (0.07, 0.15), and 0.12L (0.08, 0.16), respectively. The second COPD dose-ranging trial was a 4-week, randomized, double-blind, placebo-controlled, parallel group trial in 405 patients. Dose-related improvements in lung function were also seen, with no added benefit of the 20 mcg dose over the 10 mcg dose (Figure 1). The third COPD dose-ranging trial was a randomized, double-blind, 4-way cross-over, dose-regimen trial in 47 patients. Treatment arms included 2 mcg twice-daily, 5 mcg once-daily, 5 mcg twice-daily, and 10 mcg once-daily. There was no clear difference in treatment effect when comparing twice-daily dosing to once-daily dosing.

Figure 1 Difference from placebo for STRIVERDI RESPIMAT for FEV1 AUC0-3hr and trough FEV1 after 4 weeks

Four randomized, double-blind, placebo-controlled dose-ranging trials were performed in patients with asthma, evaluating doses from 2 to 20 mcg. Results from patients with asthma were consistent with results from dose-ranging trials in patients with COPD. STRIVERDI RESPIMAT is not indicated for asthma.

Based upon the results of the dose-ranging trials, 5 and 10 mcg doses were further evaluated in the confirmatory COPD trials.

Confirmatory Trials

The eight confirmatory trials in the STRIVERDI RESPIMAT clinical development program were four pairs of replicate, randomized, double-blind, placebo-controlled trials in 3,533 COPD patients (1,281 received the 5 mcg dose, 1,284 received the 10 mcg dose):

(i)

two replicate, placebo-controlled, parallel group, 48 week trials (Trials 1 and 2)

(ii)

two replicate, placebo- and active- [formoterol 12 mcg twice-daily] controlled, parallel group, 48-week trials (Trials 3 and 4)

(iii)

two replicate, placebo- and active- [formoterol 12 mcg twice-daily] controlled, 6-week cross-over trials (Trials 5 and 6)

(iv)

two replicate, placebo- and active- [tiotropium bromide 18 mcg once-daily] controlled, 6-week cross-over trials (Trials 7 and 8).

These eight trials enrolled patients who were 40 years of age or older with a clinical diagnosis of COPD, a smoking history of at least 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal [GOLD II – IV] and a post-bronchodilator FEV1 to FVC ratio of less than 70%).

The majority of the 3,104 patients in the 48-week trials (Trials 1 and 2, Trials 3 and 4) were male (77%), white (66%) or Asian (32%), with a mean age of 64 years. Mean post-bronchodilator FEV1 was 1.38 L (GOLD II [50%], GOLD III [40%], GOLD IV [10%]). Mean beta2-agonist responsiveness was 15% of baseline (0.16 L). With the exception of other LABAs, all pulmonary medications were allowed as concomitant therapy (e.g., tiotropium [24%], ipratropium [25%], inhaled corticosteroids [45%], xanthines [16%]); patient enrollment was stratified by tiotropium use. In all four trials, the primary efficacy endpoints were change from pre-treatment baseline in FEV1 AUC0-3 and trough (pre-dose) FEV1 (after 12 weeks in Trials 1 and 2; after 24 weeks in Trials 3 and 4).

In all four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in FEV1 AUC 0-3hr compared to placebo at week 12 (Table 2) and at week 24. In the four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in trough FEV1 compared to placebo at week 12 (Table 2; 3 of 4 trials) and at week 24 (4 trials). STRIVERDI RESPIMAT 5 mcg demonstrated a bronchodilatory treatment effect at 5 minutes after the first dose with a mean increase in FEV1 compared to placebo of 0.11L (range: 0.10L to 0.12L). The 10 mcg dose demonstrated no additional benefit over the 5 mcg dose (data not shown). Patients treated with STRIVERDI RESPIMAT 5 mcg used less rescue albuterol compared to patients treated with placebo.

In Trials 1 and 2, serial spirometric evaluations were performed pre-dose and up to 12 hours after dosing in a sub-group of 562 patients (201 patients receiving STRIVERDI RESPIMAT 5 mcg, 192 patients receiving 10 mcg, and 169 patients receiving placebo) after 12 weeks of treatment. Dosing occurred at approximately the same time of the day in the morning. The spirometric curves from Trial 1 are displayed in Figure 2.

Figure 2 FEV1 profile for STRIVERDI RESPIMAT 5 mcg and placebo at week 12 (pre-dose and up to 12 hrs post-dose) (Trial 1)

The bronchodilatory profile of STRIVERDI RESPIMAT 5 mcg over the 24 hour dosing interval was evaluated in two pairs of replicate, placebo- and active-controlled, 6 week cross-over trials in 199 patients (Trials 5 and 6) and 230 patients (Trials 7 and 8) with moderate to very severe COPD. Mean beta2-agonist responsiveness ranged from 14% -21% of baseline (0.18 to 0.22 L). All pulmonary medications were allowed as concomitant therapy with the exception of other LABAs (all trials) and anti-cholinergics (Trials 7 and 8). In all four trials, the primary endpoints were change from pre-treatment baseline in FEV1 AUC0-12hr and FEV1 AUC12-24hr after 6 weeks; although not a primary endpoint, trough FEV1 was also measured after 6 weeks. Results are shown in Table 3.

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

Not for Acute Symptoms

STRIVERDI 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 STRIVERDI 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 STRIVERDI RESPIMAT, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once-daily dosage of STRIVERDI 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.

Paradoxical Bronchospasm

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

Hypersensitivity Reactions

Inform patients that immediate hypersensitivity reactions, including angioedema, may occur after administration of STRIVERDI RESPIMAT. Advise patient to immediately discontinue STRIVERDI RESPIMAT and consult a physician.

Instructions for Administering STRIVERDI RESPIMAT

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

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

When using the unit for the first time, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. STRIVERDI RESPIMAT 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.