Tiotropium bromide and olodaterol

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# Black Box Warning

# Overview
Tiotropium bromide and olodaterol is a combination of an anticholinergic and a long-acting beta2-adrenergic agonist that is FDA approved for the treatment of of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include nasopharyngitis, cough, and back pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Tiotropium bromide and olodaterol is indicated for long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Important Limitations of Use:
- Tiotropium bromide and olodaterol is not indicated to treat acute deteriorations of COPD.
- Tiotropium bromide and olodaterol is not indicated to treat asthma. The safety and effectiveness of tiotropium bromide and olodaterol in asthma have not been established.
Dosing Information
- The recommended dose of tiotropium bromide and olodaterol is two inhalations once-daily at the same time of the day.
- Do not use tiotropium bromide and olodaterol more than two inhalations every 24 hours.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of tiotropium bromide and olodaterol in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of tiotropium bromide and olodaterol in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tiotropium bromide and olodaterol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of tiotropium bromide and olodaterol in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of tiotropium bromide and olodaterol in pediatric patients.

# Contraindications
- All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
- Tiotropium bromide and olodaterol is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product.
- In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema, itching, or rash have been reported. Hypersensitivity reactions were also reported in clinical trials with tiotropium bromide and olodaterol.

# Warnings
- Asthma-Related Death
Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death.
Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (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 long-acting beta2-adrenergic agonists, including olodaterol, one of the active ingredients in tiotropium bromide and olodaterol. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with tiotropium bromide and olodaterol has been conducted.
The safety and efficacy of tiotropium bromide and olodaterol in patients with asthma have not been established. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
- Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death.
- Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
- A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (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 long-acting beta2-adrenergic agonists, including olodaterol, one of the active ingredients in tiotropium bromide and olodaterol. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with tiotropium bromide and olodaterol has been conducted.
- The safety and efficacy of tiotropium bromide and olodaterol in patients with asthma have not been established. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
- Deterioration of Disease and Acute Episodes
Tiotropium bromide and olodaterol should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Tiotropium bromide and olodaterol has not been studied in patients with acutely deteriorating COPD. The use of tiotropium bromide and olodaterol in this setting is inappropriate.
Tiotropium bromide and olodaterol should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol, 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 tiotropium bromide and olodaterol, 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 tiotropium bromide and olodaterol no longer controls symptoms of bronchoconstriction, or the patients 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 tiotropium bromide and olodaterol beyond the recommended dose is not appropriate in this situation.
- Tiotropium bromide and olodaterol should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Tiotropium bromide and olodaterol has not been studied in patients with acutely deteriorating COPD. The use of tiotropium bromide and olodaterol in this setting is inappropriate.
- Tiotropium bromide and olodaterol should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol, 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 tiotropium bromide and olodaterol, 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 tiotropium bromide and olodaterol no longer controls symptoms of bronchoconstriction, or the patients 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 tiotropium bromide and olodaterol beyond the recommended dose is not appropriate in this situation.
- Excessive Use of Tiotropium bromide and Olodaterol and Use With Other Long-Acting Beta2-Agonists
As with other inhaled drugs containing beta2-adrenergic agents, tiotropium bromide and olodaterol 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.
- As with other inhaled drugs containing beta2-adrenergic agents, tiotropium bromide and olodaterol 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.
- Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of tiotropium bromide and olodaterol.
If such a reaction occurs, therapy with tiotropium bromide and olodaterol should be stopped at once and alternative treatments should be considered.
Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to tiotropium bromide and olodaterol.
- Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may occur after administration of tiotropium bromide and olodaterol.
- If such a reaction occurs, therapy with tiotropium bromide and olodaterol should be stopped at once and alternative treatments should be considered.
- Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to tiotropium bromide and olodaterol.
- Paradoxical Bronchospasm
As with other inhaled medicines, tiotropium bromide and olodaterol may cause paradoxical bronchospasm that may be life-threatening.
If paradoxical bronchospasm occurs, tiotropium bromide and olodaterol should be stopped immediately and alternative therapy instituted.
- As with other inhaled medicines, tiotropium bromide and olodaterol may cause paradoxical bronchospasm that may be life-threatening.
- If paradoxical bronchospasm occurs, tiotropium bromide and olodaterol should be stopped immediately and alternative therapy instituted.
- Cardiovascular Effects
Olodaterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms.
If such effects occur, tiotropium bromide and olodaterol 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.
- Olodaterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms.
- If such effects occur, tiotropium bromide and olodaterol 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.
- Coexisting Condition
Olodaterol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines.
Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Olodaterol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines.
- Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Worsening of Narrow-Angle Glaucoma
Tiotropium bromide and olodaterol should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).
Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
- Tiotropium bromide and olodaterol should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).
- Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
- Worsening of Urinary Retention
Tiotropium bromide and olodaterol should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction.
Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
- Tiotropium bromide and olodaterol should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction.
- Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
- Renal Impairment
Because tiotropium is a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide and olodaterol should be monitored closely for anticholinergic side effects.
- Because tiotropium is a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide and olodaterol should be monitored closely for anticholinergic side effects.
- Hypokalemia and Hyperglycemia
Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects.
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, which may increase the susceptibility for cardiac arrhythmias.
Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of olodaterol with the rates similar to those for placebo controls.
Olodaterol has not been investigated in patients whose diabetes mellitus is not well controlled.
- Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects.
- 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, which may increase the susceptibility for cardiac arrhythmias.
- Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of olodaterol with the rates similar to those for placebo controls.
- Olodaterol has not been investigated in patients whose diabetes mellitus is not well controlled.

# Adverse Reactions

## Clinical Trials Experience
LABA, such as olodaterol, one of the active components in tiotropium bromide and olodaterol, increase the risk of asthma-related death. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
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 tiotropium bromide and olodaterol included 7151 subjects with COPD in two 52-week active-controlled trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled cross-over trials, and four additional trials of shorter duration. A total of 1988 subjects received at least 1 dose of tiotropium bromide and olodaterol. 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. These trials included 5162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1029 were treated with tiotropium bromide and olodaterol once daily. The tiotropium bromide and olodaterol group was composed of mostly Caucasians (71.1%) with a mean age of 63.8 years and a mean percent predicted FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and olodaterol 5 mcg were included as active control arms and no placebo was used.
In these two clinical trials, 74% of patients exposed to tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol treatment group and a higher incidence rate than the active comparator groups listed.
Other adverse drug reactions in patients receiving tiotropium bromide and olodaterol that occurred in 3% of patients in clinical studies are listed below:
- Metabolism and nutrition disorders: dehydration
- Nervous system disorders: dizziness, insomnia
- Eye disorders: glaucoma, intraocular pressure increased, vision blurred
- Cardiac/vascular disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension
Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis
- Gastrointestinal disorders: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including paralytic ileus
- Skin and subcutaneous disorders: rash, pruritus, angioneurotic edema, urticaria, skin infection, and skin ulcer, dry skin, hypersensitivity (including immediate reactions)
- Musculoskeletal and connective tissue disorders: arthralgia, joint swelling
- Renal and urinary disorders: urinary retention, dysuria, and urinary tract infection

## Postmarketing Experience
There is limited information regarding Tiotropium bromide and olodaterol Postmarketing Experience in the drug label.

# Drug Interactions
- 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 tiotropium bromide and olodaterol may be potentiated.
- 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 tiotropium bromide and olodaterol may be potentiated.
- 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.
- 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.
- Non-Potassium Sparing Diuretics
The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Although the clinical significance of these effects is not known, caution is advised in the co-administration of tiotropium bromide and olodaterol with non-potassium sparing diuretics.
- The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
- Although the clinical significance of these effects is not known, caution is advised in the co-administration of tiotropium bromide and olodaterol with non-potassium sparing diuretics.
- Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs
Tiotropium bromide and olodaterol, as with other drugs containing beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents.
Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
- Tiotropium bromide and olodaterol, as with other drugs containing beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents.
- Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
- Beta-Blockers
Beta-adrenergic receptor antagonists (beta-blockers) and the olodaterol component of tiotropium bromide and olodaterol 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.
- Beta-adrenergic receptor antagonists (beta-blockers) and the olodaterol component of tiotropium bromide and olodaterol 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.
- Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications.
Therefore, avoid co-administration of tiotropium bromide and olodaterol with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.
- There is potential for an additive interaction with concomitantly used anticholinergic medications.
- Therefore, avoid co-administration of tiotropium bromide and olodaterol with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.
- 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.
Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment of tiotropium bromide and olodaterol is necessary.
- 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.
- Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment of tiotropium bromide and olodaterol is necessary.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Teratogenic Effects: Pregnancy Category C.
There are no adequate and well-controlled studies with tiotropium bromide and olodaterol or its individual components, tiotropium bromide and olodaterol, in pregnant women. Animal reproduction studies were conducted with the individual components of tiotropium bromide and olodaterol, tiotropium bromide and olodaterol. Tiotropium bromide and olodaterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Tiotropium
No evidence of structural alterations was observed in rats and rabbits at approximately 790 and 8 times the recommended human daily inhalation dose (RHDID; on a mcg/m2 basis at maternal inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively). 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 approximately 40 times the RHDID (on a mcg/m2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at approximately 430 times the RHDID (on a mcg/m2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the RHDID (on a mcg/m2 basis at maternal inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).
Olodaterol
Olodaterol was not teratogenic in rats at approximately 2731 times the RHDID (on an AUC basis at a maternal inhalation dose of 1054 mcg/kg/day). Placental transfer of olodaterol was observed in pregnant rats.
Olodaterol has been shown to be teratogenic in New Zealand rabbits at approximately 7130 times the RHDID in adults (on an AUC basis at a maternal inhalation dose of 2489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at approximately 1353 times the RHDID in adults (on an AUC basis at a maternal inhalation dose of 974 mcg/kg/day).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiotropium bromide and olodaterol in women who are pregnant.

### Labor and Delivery
There are no adequate and well-controlled human studies that have investigated the effects of tiotropium bromide and olodaterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of tiotropium bromide and olodaterol during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

### Nursing Mothers
Clinical data from nursing women or infants exposed to tiotropium bromide and olodaterol or its individual active components are not available. Tiotropium, olodaterol, and metabolites of olodaterol are excreted into the milk of lactating rats. It is not known whether these compounds are excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if tiotropium bromide and olodaterol is administered to a nursing woman.

### Pediatric Use
COPD does not normally occur in children. The safety and effectiveness of tiotropium bromide and olodaterol in the pediatric population has not been established.

### Geriatic Use
Based on available data, no adjustment of tiotropium bromide and olodaterol dosage in geriatric patients is warranted.
Of the 1029 patients who received tiotropium bromide and olodaterol 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.

### Gender
There is no FDA guidance on the use of Tiotropium bromide and olodaterol with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Tiotropium bromide and olodaterol with respect to specific racial populations.

### Renal Impairment
No dose adjustment is required for patients with renal impairment. However, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide and olodaterol should be monitored closely for anticholinergic side effects.

### Hepatic Impairment
No dose adjustment is needed in patients with mild and moderate hepatic impairment. A study in subjects with severe hepatic impairment was not performed.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tiotropium bromide and olodaterol in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Tiotropium bromide and olodaterol in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- For oral inhalation only.
- Prior to first use, the tiotropium bromide and olodaterol cartridge is inserted into the tiotropium bromide and olodaterol 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.
- No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium bromide and olodaterol should be monitored closely for anticholinergic effects.

### Monitoring
There is limited information regarding Tiotropium bromide and olodaterol Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Tiotropium bromide and olodaterol and IV administrations.

# Overdosage
The risks associated with overdosage for the individual components described below apply to the combination drug of tiotropium bromide and olodaterol.
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  manner, were observed following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.
Olodaterol
The expected signs and symptoms with overdosage of olodaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of olodaterol.
Treatment of overdosage consists of discontinuation of tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol. Cardiac monitoring is recommended in cases of overdosage.

# Pharmacology

## Mechanism of Action
The properties described below for the individual components apply to the combination of tiotropium bromide and olodaterol. 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, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-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 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 2299-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 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.

## Structure
The drug substance tiotropium bromide monohydrate is chemically described as (1, 2, 4, 5, 7)-7--9,9-dimethyl-3-oxa-9-azoniatricyclo nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is:
Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br - H2O.
The drug substance olodaterol hydrochloride is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8--amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094. The structural formula is:

## Pharmacodynamics
Cardiac Electrophysiology
Tiotropium Bromide and Olodaterol
In two 52-week randomized, double-blind trials using tiotropium bromide and olodaterol that enrolled 5162 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 tiotropium bromide and olodaterol 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 3060 msec was higher in the tiotropium group as compared with placebo. This difference was apparent using both the Bazett (QTcB)  and Fredericia (QTcF)  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.

## Pharmacokinetics
When tiotropium bromide and olodaterol 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 (1110 L), suggesting extensive distribution into tissue. In vitro binding of  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 CYP2D6 and CYP3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP2D6 and CYP3A4 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 CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
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 beta2-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 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 18.6% (0.932 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 Cmax from COPD patients is 7.5 hours.
Following intravenous administration of -labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5% to 7% of the dose.
Drug Interactions
Tiotropium Bromide and Olodaterol:
Pharmacokinetic drug interaction studies with tiotropium bromide and olodaterol 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 AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium.
Common concomitant medications (long-acting beta2-adrenergic agonists (LABA), inhaled corticosterioids (ICS)) used by patients with COPD were not found to alter the exposure to tiotropium.
Olodaterol:
Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP2C9 and ketoconazole as a potent P-gp (and CYP3A4, CYP2C8, CYP2C9) inhibitor.
Fluconazole:
Co-administration of 400 mg fluconazole once a day for 14 days had no relevant effect on systemic exposure to olodaterol.
Ketoconazole:
Co-administration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
Tiotropium: Co-administration of tiotropium bromide, delivered as a fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.
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 AUC0-6,ss and Cmax,ss values.
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). In COPD patients with severe renal impairment (CLCR <30 mL/min), a single intravenous administration of tiotropium bromide resulted in 94% higher AUC0-4 and 52% higher Cmax compared to COPD patients with normal renal function.
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 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.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tiotropium Bromide and Olodaterol:
No studies of the carcinogenicity, in vitro mutagenicity, or impairment of fertility were conducted with tiotropium bromide and olodaterol, 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/m2 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/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 4 times than the RHDID on a mcg/m2 basis). The fertility index; however, was not affected at inhalation doses up to 1689 mg/kg/day (approximately 760 times the RHDID on a mcg/m2 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 beta2-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 3068 mcg/kg/day (approximately 2322 times the RHDID on an AUC basis).

# Clinical Studies
The safety and efficacy of tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol 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 5162 COPD patients.
Dose-Ranging Trials
Dose selection for tiotropium bromide and olodaterol was primarily based on trials for the individual components, tiotropium bromide and olodaterol. Dose selection was also supported by two randomized, double-blind, active-controlled, 4-week trials. In one trial in 232 patients with COPD, three tiotropium doses (1.25, 2.5, and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy. Results demonstrated improvement in trough FEV1 for the combination when compared to olodaterol alone. The difference in trough FEV1 for the tiotropium bromide/olodaterol doses of 1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively. In the second trial in 360 patients with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to tiotropium monotherapy. The difference in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L (95% CI -0.029, 0.076), 0.033 L (-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively. Results of these trials supported the evaluation of once-daily doses of tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.
Confirmatory Trials:
A total of 5162 COPD patients (1029 receiving tiotropium bromide and olodaterol, 1038 receiving olodaterol 5 mcg, and 1033 receiving tiotropium bromide 5 mcg) were studied in two confirmatory trials of tiotropium bromide and olodaterol. Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials that compared tiotropium bromide and olodaterol to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products were administered via the RESPIMAT inhaler.
The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal ; post-bronchodilator FEV1 to FVC ratio of less than 70%). All treatments were administered once daily in the morning. The primary endpoints were changed from baseline in FEV1 AUC0-3hr and trough FEV1 after 24-weeks of treatment.
The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV1 was 1.37 L (GOLD 2 , GOLD 3 , GOLD 4 ). Mean beta2-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids  and xanthines .
In both Trials 1 and 2, tiotropium bromide and olodaterol demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg (Table 2). The increased bronchodilator effects of tiotropium bromide and olodaterol compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period. Tiotropium bromide and olodaterol displayed a mean increase in FEV1 from baseline of 0.137 L (range: 0.133-0.140 L) within 5 minutes after the first dose. Patients treated with tiotropium bromide and olodaterol used less rescue medication compared to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.
For the subset of patients (n=521) who completed extended lung function measurements up to 12 hours post-dose, tiotropium bromide and olodaterol showed a significantly greater FEV1 response compared to tiotropium 5 mcg and olodaterol 5 mcg over the full 24-hour dosing interval. Results from Trial 2 are shown in Figure 1.

# How Supplied
The drug product, tiotropium bromide and olodaterol, is composed of a sterile aqueous solution of tiotropium bromide and olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (tiotropium bromide and olodaterol cartridge) for use with the tiotropium bromide and olodaterol inhaler.
Excipients include water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid.
The tiotropium bromide and olodaterol cartridge is only intended for use with the tiotropium bromide and olodaterol inhaler. The tiotropium bromide and olodaterol inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The tiotropium bromide and olodaterol inhaler has a light green-colored cap.
When used with the tiotropium bromide and olodaterol inhaler each cartridge, containing 4 grams of sterile aqueous solution, delivers the labeled number of metered actuations after preparation for use. Each dose (one dose equals two actuations) from the tiotropium bromide and olodaterol inhaler delivers 5 mcg tiotropium and 5 mcg olodaterol in 22.1 mcL from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
Tiotropium bromide and olodaterol cartridge and one tiotropium bromide and olodaterol inhaler.
The tiotropium bromide and olodaterol cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The tiotropium bromide and olodaterol cartridge is only intended for use with the tiotropium bromide and olodaterol inhaler and should not be interchanged with any other RESPIMAT device delivered product.
The tiotropium bromide and olodaterol inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The light green-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the tiotropium bromide and olodaterol cartridge.
Tiotropium Bromide and Olodaterol Inhalation Spray is available as: Tiotropium Bromide and Olodaterol Inhalation Spray: 60 metered actuations (NDC 0597-0155-61)
The tiotropium bromide and olodaterol cartridge has a net fill weight of at least 4 grams and when used with the tiotropium bromide and olodaterol inhaler, is designed to deliver the labeled number of metered actuations after preparation for use.
When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
After assembly, the tiotropium bromide and olodaterol inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
Keep out of reach of children. Do not spray into eyes.

## Storage
Store at 25C (77F); excursions permitted to 15C to 30C (59F to 86F). Avoid freezing.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
- Asthma-Related Death
Inform patients that LABAs, such as tiotropium bromide and olodaterol, increase the risk of asthma-related death.
Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
- Inform patients that LABAs, such as tiotropium bromide and olodaterol, increase the risk of asthma-related death.
- Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.
- Not for Acute Symptoms
Tiotropium bromide and olodaterol 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-agonists 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 tiotropium bromide and olodaterol without physician/provider guidance since symptoms may recur after discontinuation.
- Tiotropium bromide and olodaterol 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-agonists 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
- 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 tiotropium bromide and olodaterol 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 tiotropium bromide and olodaterol, other inhaled medications containing long-acting beta2-agonists should not be used.
Patients should not use more than the recommended once-daily dose of tiotropium bromide and olodaterol. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
- 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 tiotropium bromide and olodaterol, other inhaled medications containing long-acting beta2-agonists should not be used.
- Patients should not use more than the recommended once-daily dose of tiotropium bromide and olodaterol. 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.
- 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 tiotropium bromide and olodaterol can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue tiotropium bromide and olodaterol.
- Inform patients that tiotropium bromide and olodaterol can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue tiotropium bromide and olodaterol.
- Urinary Retention
Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction.
Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
- Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction.
- Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
- Visual Effects
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma.
Inform patients to consult a physician immediately should any of these signs and symptoms develop.
Advise patients that miotic eye drops alone are not considered to be effective treatment.
Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.
Since dizziness and blurred vision may occur with the use of tiotropium bromide and olodaterol, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.
- Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma.
- Inform patients to consult a physician immediately should any of these signs and symptoms develop.
- Advise patients that miotic eye drops alone are not considered to be effective treatment.
- Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.
- Since dizziness and blurred vision may occur with the use of tiotropium bromide and olodaterol, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.
- Instructions for Administering Tiotropium Bromide and Olodaterol
It is important for patients to understand how to correctly administer tiotropium bromide and olodaterol inhalation spray using the tiotropium bromide and olodaterol inhaler.
Instruct patients that tiotropium bromide and olodaterol inhalation spray should only be administered via the tiotropium bromide and olodaterol inhaler and the tiotropium bromide and olodaterol inhaler should not be used for administering other medications.
Instruct patients that priming tiotropium bromide and olodaterol is essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the tiotropium bromide and olodaterol cartridge is inserted into the tiotropium bromide and olodaterol inhaler and the unit is primed.
Tiotropium bromide and olodaterol patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times. The unit is then considered primed and ready for use.
If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use.
If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- It is important for patients to understand how to correctly administer tiotropium bromide and olodaterol inhalation spray using the tiotropium bromide and olodaterol inhaler.
- Instruct patients that tiotropium bromide and olodaterol inhalation spray should only be administered via the tiotropium bromide and olodaterol inhaler and the tiotropium bromide and olodaterol inhaler should not be used for administering other medications.
- Instruct patients that priming tiotropium bromide and olodaterol is essential to ensure appropriate content of the medication in each actuation.
- When using the unit for the first time, the tiotropium bromide and olodaterol cartridge is inserted into the tiotropium bromide and olodaterol inhaler and the unit is primed.
- Tiotropium bromide and olodaterol patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times. The unit is then considered primed and ready for use.
- If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use.
- If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

# Precautions with Alcohol
Alcohol-Tiotropium bromide and olodaterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
STIOLTO RESPIMAT

# Look-Alike Drug Names
There is limited information regarding Tiotropium bromide and olodaterol Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price