AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Tiotropium Bromide

Chemical Name:

• di-2-thienylglycolate-6β,7β-Epoxy-3β-hydroxy-8-methyl-1α H ,5α H -tropanium bromide

Molecular Formula:

• C₁₉H₂₂BrNO₄S₂

Tiotropium bromide, a synthetic quaternary ammonium antimuscarinic agent, is a long-acting orally inhaled bronchodilator.1,23,24

Bronchospasm

Chronic Obstructive Pulmonary Disease

Tiotropium bromide is used as a bronchodilator alone or in fixed combination with olodaterol hydrochloride for the long-term maintenance treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.1,15,23,24 Tiotropium bromide alone also is used to reduce exacerbations of COPD in patients with a history of such exacerbations.1,23 In patients with moderate to severe COPD (e.g., forced expiratory volume in 1 second [FEV₁] 30 to less than 80% of predicted15 or, alternatively, less than 60% of predicted)18 who have persistent symptoms not relieved by as-needed therapy with ipratropium and/or a selective, short-acting inhaled β₂-agonist, maintenance monotherapy with a long-acting bronchodilator (e.g., orally inhaled salmeterol, formoterol, or tiotropium) or an inhaled corticosteroid may be used,15,18 and a short-acting, selective inhaled β₂-agonist is used as needed for immediate symptom relief.15 Maintenance therapy with long-acting bronchodilators in patients with moderate to severe COPD is more effective and more convenient than regular therapy with short-acting bronchodilators.13,15,18 Data are insufficient to favor one maintenance monotherapy over another for use in such patients.15,18 Some clinicians recommend therapy with a combination of several long-acting bronchodilators such as tiotropium and a long-acting β-adrenergic agonist in selected patients with inadequate response.13,14,15 In patients with severe to very severe COPD (e.g., FEV₁ less than 30 to less than 50% of predicted), some clinicians recommend addition of an inhaled corticosteroid to maintenance therapy with one or more long-acting bronchodilators given separately or in fixed combination;12,14,15 however, the benefits of combination therapy over monotherapy have not been consistently demonstrated.18 If symptoms are not adequately controlled with inhaled corticosteroids and a long-acting bronchodilator or if limiting adverse effects occur, addition or substitution of extended-release oral theophylline may be considered.12,14,15 Orally inhaled tiotropium alone or in combination with olodaterol is not indicated for treatment of acute episodes of bronchospasm or acute deterioration of COPD;1,23,24 a drug with a more rapid onset of action (e.g., a short-acting β-adrenergic agonist) may be preferred in such cases.2,3,7,8

Currently available data indicate that tiotropium improves lung function (e.g., as determined by FEV₁) in patients with COPD compared with ipratropium or placebo.1,4,6,7,8,11,12 Such improvement in lung function has been maintained throughout the 24-hour dosing interval and for treatment periods of up to 1 year with no evidence of tolerance.1,6 In some studies, treatment with tiotropium also has been associated with a reduction in the need for supplemental short-acting β₂ agonists compared with placebo.1,6

In several long-term (e.g., 1-year) comparative studies in patients with COPD, orally inhaled tiotropium (18 mcg once daily) improved lung function (e.g., as determined by mean change in trough FEV₁, morning and evening peak expiratory flow rate [PEFR]) to a greater degree than ipratropium bromide (36 mcg 4 times daily) oral inhalation aerosol.1,4,7 In addition, treatment with tiotropium reduced dyspnea and the number of COPD exacerbations and increased the time to a first exacerbation compared with ipratropium bromide aerosol.4

In two 6-month comparative trials in patients with COPD receiving either orally inhaled tiotropium (18 mcg once daily) or salmeterol (50 mcg twice daily), tiotropium was more effective in improving bronchodilation (e.g., FEV₁, evening PEFR) than salmeterol therapy or placebo.7,8,9,10,12 In addition, while tiotropium or salmeterol each reduced dyspnea and improved FEV₁ compared with placebo, tiotropium also was more effective than placebo in reducing COPD exacerbations and all-cause hospital admissions and improving quality-of-life scores in these trials.7,8,9,10

The efficacy of tiotropium oral inhalation powder for reducing exacerbations in patients with COPD also has been studied in 2 randomized, placebo-controlled clinical trials: a 6-month trial including 1829 patients and a 4-year trial including 5992 patients.1,27 In the 4-year study, long-term effects on lung function and other outcomes also were evaluated.27 In both studies, patients were allowed to use their prescribed respiratory medications (e.g., short- and long-acting β-agonists, inhaled and systemic corticosteroids, theophyllines) except for inhaled anticholinergic agents.1,27 In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) including more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic corticosteroids, or hospitalization.1 Patients were 40-90 years of age, 99% were male, and 91% were white, with a mean pre-bronchodilator FEV₁ of 36% of predicted (range: 8-93%).1 The primary end points were the proportion of patients with COPD exacerbations and the proportion of patients with hospitalization due to COPD exacerbations.1 The proportion of patients with COPD exacerbations was substantially lower in patients receiving tiotropium than in patients receiving placebo (27.9 versus 32.3%).1 The proportion of patients with hospitalization due to COPD exacerbations (7 or 9.5% in patients receiving tiotropium or placebo, respectively) was not substantially different in the 2 groups.1

In the 4-year trial, patients were 40-88 years of age, 75% were male, and 90% were white with a mean pre-bronchodilator FEV₁ of 39% of predicted (range: 9-76%).1 The primary efficacy end points (i.e., yearly rate of decline in pre- and post-bronchodilator FEV₁) did not differ between the 2 study groups.1,27 However, improvements in trough (pre-dose) FEV₁ (adjusted means over time: 87-103 mL) were maintained over the 4 years of the study in patients receiving tiotropium.1,27 COPD exacerbations were a secondary end point in this trial and were defined as an increase or new onset of more than one of the following respiratory symptoms: cough, sputum, sputum purulence, wheezing, and dyspnea, with a duration of 3 or more days requiring treatment with antibiotics and/or systemic corticosteroids.1,27 The risk of exacerbation and of exacerbation-related hospitalization both were reduced by 14% in patients receiving tiotropium compared with those receiving placebo; in addition, median time to first exacerbation was longer in patients receiving tiotropium compared with placebo (16.7 versus 12.5 months).1,27 All-cause mortality was similar in patients receiving tiotropium or placebo.1,27

In a long-term, randomized, double-blind, double-dummy, active-controlled trial (Tiotropium Safety and Performance in Respimat [TIOSPIR]) with an observation period of up to 3 years, all-cause mortality was found to be similar in patients receiving tiotropium oral inhalation powder compared with those receiving tiotropium oral inhalation solution.1,23,26

Efficacy of tiotropium oral inhalation solution was based principally on 5 confirmatory, placebo- and active-controlled studies of 12-48 weeks' duration.23 In the randomized, double-blind, placebo- and/or active-controlled trials, efficacy of tiotropium oral inhalation solution was evaluated in 6614 patients with COPD; patients were 40 years of age or older, had a history of smoking greater than 10 pack-years, an FEV₁ of 60% of predicted or less, and a baseline FEV₁/forced vital capacity (FVC) of 0.7 or less.23 The primary outcome measure was the change from baseline in trough FEV₁.23 All study medications were administered once daily in the morning via the Respimat^® inhaler.23 In these studies, trough FEV₁ was improved by 100-140 mL with tiotropium compared with placebo.23 In the 3 trials that evaluated COPD exacerbations, tiotropium oral inhalation solution at a dosage of 5 mcg once daily reduced the rate of exacerbations compared with placebo.23

Efficacy of tiotropium in fixed combination with olodaterol hydrochloride was based principally on 2 dose-ranging studies of 4 weeks' duration and 2 confirmatory, active-controlled studies of 52 weeks' duration.24 In the 2 randomized, double-blind, active-controlled, parallel-group trials, efficacy of tiotropium in combination with olodaterol was evaluated in 5162 patients 40 years of age or older with moderate to very severe COPD.24,25 The primary outcome measures were the change from baseline in FEV₁ AUC from 0-3 hours and trough FEV₁ after 24 weeks of therapy.24,25 All study medications were administered once daily in the morning via the Respimat^® inhaler.24,25 In these studies, FEV₁ AUC from 0-3 hours at 24 weeks was improved by 256-268 mL with orally inhaled tiotropium 5 mcg in combination with olodaterol 5 mcg compared with improvements of 139-165 or 133-136 mL with either tiotropium 5 mcg or olodaterol 5 mcg, respectively, alone.24,25 Trough FEV₁ at 24 weeks was improved by 136-145 mL with tiotropium in combination with olodaterol compared with improvements of 65-96 or 54-57 mL with either tiotropium or olodaterol, respectively, alone.24,25 The increased bronchodilator effects observed with tiotropium in combination with olodaterol were maintained throughout the 52-week studies.24,25 Patients receiving the fixed combination of tiotropium and olodaterol required less albuterol as rescue therapy compared with those receiving either tiotropium or olodaterol alone.24,25

For additional information on the treatment of COPD, see Uses: Chronic Obstructive Pulmonary Disease, in Ipratropium Bromide 12:08.08.

Asthma

Tiotropium bromide oral inhalation solution is used for the long-term maintenance treatment of reversible bronchospasm associated with asthma.23 Orally inhaled tiotropium solution is not indicated for the treatment of acute episodes of bronchospasm; a drug with a more rapid onset of action (e.g., a short-acting β-adrenergic agonist) should be used in such cases.23 Tiotropium bromide in fixed combination with olodaterol hydrochloride is not indicated for the treatment of asthma.24

Efficacy of tiotropium oral inhalation solution for the treatment of persistent asthma in adults was based principally on 5 randomized, double-blind, placebo-controlled studies of 12-48 weeks' duration.23 In the randomized, double-blind, placebo- and/or active-controlled trials, efficacy of orally inhaled tiotropium solution was evaluated in 3476 patients 18-75 years of age with a diagnosis of asthma who were receiving baseline therapy with at least inhaled corticosteroids.23 The primary outcome measure in all of the studies was the change from baseline in peak FEV₁ at 0-3 hours at week 12 or 24.23 In 2 trials, an additional primary outcome measure was change from baseline in trough FEV₁ at week 24.23 Patients randomized to receive tiotropium oral inhalation solution received the drug once daily via the Respimat^® inhaler.23 In these studies, peak FEV₁ at 0-3 hours was improved by 160-240 mL with tiotropium compared with placebo.23 In the 3 trials that evaluated orally inhaled tiotropium dosages of 2.5 or 5 mcg once daily, FEV₁ response was generally lower for the 5-mcg dose compared with the 2.5-mcg dose.23 Improvement in lung function with tiotropium compared with placebo was maintained for 24 hours.23 The bronchodilator effects of tiotropium 2.5 mcg once daily were apparent after the first dose; however, maximum bronchodilator effect was not achieved for up to 4-8 weeks.23

Efficacy of tiotropium oral inhalation solution for the treatment of persistent asthma in pediatric patients was based on extrapolation of efficacy in adults and on several randomized, double-blind, placebo-controlled studies of 12-48 weeks' duration.23 The primary outcome measure in these studies was the change from baseline in peak FEV₁ at 0-3 hours at week 12 or 24.23 In adolescents, 2 clinical studies evaluated efficacy of orally inhaled tiotropium solution in 789 patients 12-17 years of age with a diagnosis of asthma who were receiving baseline therapy with at least inhaled corticosteroids.23 Patients randomized to receive tiotropium oral inhalation solution were administered 2.5 or 5 mcg of the drug once daily via the Respimat^® inhaler.23 In these studies, peak FEV₁ at 0-3 hours was improved by 110-130 mL with tiotropium 2.5 mcg once daily compared with placebo.23

In children, 2 clinical studies evaluated efficacy of tiotropium oral inhalation solution in 801 patients 6-11 years of age with a diagnosis of asthma who were receiving baseline therapy with at least inhaled corticosteroids.23 Patients randomized to receive tiotropium oral inhalation solution were administered 2.5 or 5 mcg of the drug once daily via the Respimat^® inhaler.23 In the 48-week study, peak FEV₁ at 0-3 hours was improved by 170 mL with tiotropium 2.5 mcg once daily compared with placebo.23 The efficacy results from the 12-week study were not statistically significant.23

General

Dosage of tiotropium bromide, which is commercially available as the monohydrate, is expressed in terms of anhydrous tiotropium.1,11,23

Although each capsule under the foil lid of the blister strip contains 18 mcg of tiotropium as an inhalation powder, the precise amount of drug delivered to the lungs with each activation of the HandiHaler^® device depends on factors such as the patient's inspiratory flow.1 Peak inspiratory flow through the HandiHaler^® device also varies according to the exposure time of the capsule outside of the blister pack.1,11 Using standardized in vitro testing at a flow rate of 39 L/minute for 3.1 seconds, the HandiHaler^® inhaler delivered a mean of 10.4 mcg of tiotropium per activation from the mouthpiece.1

Each activation of the oral inhalation device containing tiotropium bromide oral inhalation solution (Spiriva^® Respimat^®) delivers 1.56 or 3.1 mcg of tiotropium bromide monohydrate (equivalent to 1.25 or 2.5 mcg, respectively, of tiotropium) from the mouthpiece.23 Each activation of the oral inhalation device containing tiotropium and olodaterol in fixed combination (Stiolto^® Respimat^®) delivers 3.1 mcg of tiotropium bromide monohydrate (equivalent to 2.5 mcg of tiotropium) and 2.7 mcg of olodaterol hydrochloride (equivalent to 2.5 mcg of olodaterol) from the mouthpiece.24 The precise amount of drug delivered to the lungs with each activation of the inhaler device depends on factors such as the patient's coordination between actuation of the inhaler and inspiration through the delivery system.23,24 Because the Respimat^® inhaler mechanically releases the dose, the delivered dose is independent of the patient's inspiratory effort.23,24 The commercially available inhalers deliver 60 metered sprays (not including the initial priming actuations) equivalent to 30 doses (2 actuations per dose) of the drug.23,24

Administration

Oral Inhalation via Dry Powder Inhaler

Tiotropium bromide dry-powder capsules are administered by oral inhalation only using a special oral inhalation device (HandiHaler^®) that delivers powdered drug from capsules.1,16 Tiotropium bromide capsules for oral inhalation must not be taken orally, as the intended effects on the lungs will not be obtained.1,16

To obtain optimal benefit, the patient should be given a copy of the patient instructions provided by the manufacturer.1 To use the inhaler, the dust cap of the inhaler should be opened by pressing the green piercing button.1 The dust cap on the side opposite the hinge on the gray base should be pulled upward to expose the mouthpiece.1 The mouthpiece of the inhaler should be opened by pulling the mouthpiece ridge upward on the side opposite the hinge on the gray base to expose the center chamber.1 The blister card should be carefully opened to expose only one capsule immediately before use.1 The capsule contains only a small amount of powder and should not be opened.1 The capsule should then be placed into the center chamber of the inhaler.1 After the capsule is loaded, the inhaler mouthpiece should be closed firmly until it snaps (clicks) into position; the dust cap is left open (up).1 Patients should push down on the mouthpiece ridge to make sure that the mouthpiece is seated in the gray base of the inhaler.1 While holding the inhaler with the seated mouthpiece upward, the green piercing button on the side of the inhaler should be completely depressed (green button is flush with the gray base of the inhaler) and then released.1 The button pierces the capsule and disperses the powdered drug upon inspiration; the piercing button should not be pressed more than one time and the Handihaler^® device should not be shaken.1,11 Piercing the capsule may produce small gelatin pieces, which may pass into the mouth or throat during inhalation of the drug; the gelatin pieces should not cause any harm.1

Before inhaling the dose, the patient should exhale as completely as possible, being careful not to exhale into the HandiHaler^® device.1 The inhaler device should be held along the sides of the gray base taking care not to block the air intake vents near the mouthpiece ridge.1 With the head kept level, the patient should place the mouthpiece of the inhaler between the lips (inhaler is in horizontal position) and inhale deeply and slowly through the inhaler at a rate sufficient to hear or feel the loaded capsule vibrate.1,11 Pressure from the inhalation will disperse drug from the center chamber into the air stream created by the patient's inhalation.1 After a complete inhalation, the patient should remove the inhaler from the mouth and hold their breath for a few seconds, then resume normal breathing.1 The patient should breathe out completely and inhale once again to ensure full delivery of the powder from the same loaded, pierced capsule.1 The green piercing button should not be pressed again .1 Upon completion of the second inhalation, the patient should open the mouthpiece and tip the inhaler device to dispose of the used capsule.1 The mouthpiece and dust cap of the inhaler device should then be closed.1

If the patient does not feel or hear the capsule vibrate upon inhalation, the inhaler device should be tapped gently on a table while holding the device in an upright position.1 The patient then should check to see that the mouthpiece is properly seated in the gray base.1 The patient should attempt to inhale through the device again.1 If capsule vibration still cannot be heard or felt during inhalation, the capsule should be discarded and the base of the device should be opened by lifting the green piercing button; the center chamber should be checked for pieces of the capsule.1 The device should be turned upside down and gently but firmly tapped to remove any capsule pieces, then the clinician should be contacted for instructions.1 (See Advice to Patients.)

Dry-powder capsules for oral inhalation should be left in foil-sealed blisters until immediately before use.1 Used or unused dry-powder capsules should not be stored in the inhaler device.1 The foil of the blister pack should not be cut nor should sharp objects be used to remove the capsule selected for dosing.1 If additional capsules are inadvertently opened and exposed to air (i.e., not intended for immediate use), they should be discarded since the effectiveness of the drug in those capsules may be reduced.1,11

If patients taking tiotropium do not experience an improvement in control of COPD, a clinician should make sure that the patient is inhaling the drug using the oral inhaler rather than swallowing the dry-powder capsules.16 (See Accidental Oral Ingestion under Warnings/Precautions, in Cautions.)

The HandiHaler^® device should be cleaned as needed.1 The dust cap and mouthpiece should be opened, and then the base should be opened by lifting the green piercing button.1 Any capsule pieces or powder buildup in the center chamber should be tapped out.1 The inhaler should be rinsed with warm water (cleaning agents or detergents should not be used), pressing the green piercing button a few times so that the center chamber and piercing needle are under the running water to remove any remaining powder or capsule pieces.1 The inhaler should be dried thoroughly and the dust cap, mouthpiece, and gray base left open and fully spread out to air dry for 24 hours.1 A hair dryer should not be used to dry the device.1 The inhaler should not be used when wet.1 If needed, the outside of the mouthpiece may be cleaned with a clean, damp cloth.1,11

Oral Inhalation via Metered-Dose Inhaler

Tiotropium bromide solution is administered by oral inhalation using a specific inhaler (Spiriva^® Respimat^®) that delivers a metered-dose spray.23 Tiotropium bromide in fixed combination with olodaterol hydrochloride is administered by oral inhalation using a specific inhaler (Stiolto^® Respimat^®) that delivers a metered-dose spray.24 Both inhalers deliver the drugs in an aqueous solution and mechanically produce a fine aerosol mist from the orally inhaled solution.23,24 Tiotropium bromide alone or in fixed combination with olodaterol should be administered once daily at the same time every day.23,24

Before first use of either Spiriva^® Respimat^® or Stiolto^® Respimat^®, the inhaler cartridge should be placed into the inhaler.23,24 The manufacturer's prescribing information should be consulted for detailed information on preparation of the inhalers.23,24 The discard date (3 months after the cartridge is inserted into the inhaler) should be written on the inhaler label.23,24

After the cartridge has been inserted into either the Spiriva^® Respimat^® or the Stiolto^® Respimat^® inhaler, the unit must be primed prior to first use.23,24 Beginning with the inhaler held upright and the cap closed, the clear base should be turned in the direction of the black arrows on the label until a click is heard (one-half turn).23,24 The cap should then be flipped until it fully snaps open, the inhaler should be pointed away from the face, the dose release button pressed, and then the cap closed.23,24 These steps (turning the clear base until it clicks, opening the cap, actuating the inhaler, and replacing the cap) should be repeated until a spray is visible, and then for 3 additional times.23,24 The initial actuation step of the priming process (without the 3 additional repetitions) should be repeated after a period of nonuse (i.e., more than 3 days).23,24 If the inhaler is not used for more than 21 days, the entire initial priming process should be repeated.23,24

To administer a dose of tiotropium alone or in fixed combination with olodaterol, the patient should hold the inhaler upright with the cap closed and turn the clear base in the direction of the black arrows on the label until a click is heard (one-half turn).23,24 The cap should be flipped until it snaps fully open.23,24 Before inhaling the dose, the patient should exhale slowly and completely.23,24 The patient should then close the lips around the end of the mouthpiece, without covering the air vents.23,24 With the inhaler pointing toward the back of the throat, the patient should press the dose release button while taking a slow, deep inhalation through the mouth; the patient should continue inhaling as long as possible.23,24 The patient should then hold the breath for 10 seconds (or as long as comfortable).23,24 This procedure should be repeated once more to administer the full dose (2 inhalations) of tiotropium alone or in combination with olodaterol.23,24 After the full dose is administered, the cap of the inhaler should be closed.23,24

The mouthpiece of either the Spiriva^® Respimat^® or the Stiolto^® Respimat^® inhaler, including the metal part inside, should be cleaned using only a damp tissue or cloth at least once weekly.23,24 If the outside of the inhaler gets dirty, it can be wiped with a damp cloth.23,24 The function of the inhaler is not affected by minor discoloration in the mouthpiece.23,24

Dosage

Chronic Obstructive Pulmonary Disease

For the long-term management of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), the usual dosage of tiotropium oral inhalation powder in adults is 18 mcg (2 inhalations, the contents of one capsule) once daily via the HandiHaler^® device.1,11,15 No more than one dose should be taken in a 24-hour period.1 Orally inhaled tiotropium powder should not be used for the treatment of acute episodes of bronchospasm.1

For the long-term management of reversible bronchospasm associated with COPD, the usual dosage of tiotropium oral inhalation solution in adults is 5 mcg (2 inhalations of the 2.5 mcg per metered-dose spray) once daily via the Respimat^® device.23 No more than one dose should be taken in a 24-hour period.23 Orally inhaled tiotropium solution should not be used for the treatment of acute episodes of bronchospasm.23

Asthma

For the long-term management of reversible bronchospasm associated with asthma, the usual dosage of tiotropium oral inhalation solution in patients 6 years of age or older is 2.5 mcg (2 inhalations of the 1.25 mcg per metered-dose spray) once daily via the Respimat^® device.23 No more than one dose (2 inhalations) should be taken in a 24-hour period.23 Orally inhaled tiotropium solution should not be used for the treatment of acute episodes of bronchospasm.23

Special Populations

The manufacturer states that adjustment of tiotropium dosage is not necessary in geriatric patients or patients with hepatic or renal impairment.1,23 24 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Known hypersensitivity to tiotropium, ipratropium, or any ingredient in the formulation.1,23,24

Warnings/Precautions

Sensitivity Reactions

Immediate hypersensitivity reactions, including angioedema (e.g., swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, anaphylaxis, or itching, may occur after administration of tiotropium.1,23,24 If such a reaction occurs, the drug should be discontinued immediately and alternative therapy considered.1,23,24

Patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for hypersensitivity reactions.1 23,24 In addition, tiotropium oral inhalation powder (Spiriva^® HandiHaler^®) should be used with caution in patients with severe hypersensitivity to milk proteins.1

Use of Fixed Combinations

When tiotropium is used in fixed combination with olodaterol, the usual cautions, precautions, contraindications, and interactions associated with olodaterol must be considered.24 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.24

Acute Bronchospasm

Tiotropium bromide should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm).1,23,24

Possible Increased Risk of Stroke, Mortality, and/or Cardiovascular Events

While data are conflicting, a possible increased risk of stroke has been identified by the manufacturer from ongoing safety monitoring and pooled analysis of placebo-controlled trials in patients receiving tiotropium therapy.19 Other observational data have suggested an increased risk of mortality and/or cardiovascular events in patients receiving the drug.20,21

Analysis of data on approximately 13,500 patients with COPD in 29 studies indicated a stroke case rate of 8 or 6 per 1000 patient-years of exposure in patients receiving tiotropium or placebo, respectively, representing an absolute excess risk of 2 additional strokes per 1000 patient-years.19 In addition, data from an observational study involving over 32,000 patients and another pooled analysis of 17 studies enrolling almost 15,000 patients have shown an increased risk of mortality and/or cardiovascular events in patients receiving inhaled anticholinergic agents, including tiotropium bromide.20,21 However, the results of a placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT]) in approximately 6000 patients with COPD did not reveal an increased risk of stroke, myocardial infarction (MI), or cardiovascular death with tiotropium bromide.19,27,28 Based on a review of the UPLIFT trial, FDA has concluded that the available data do not support an association between the use of tiotropium oral inhalation powder and an increased risk of stroke, MI, or cardiovascular death.28

An increased risk of mortality with tiotropium oral inhalation solution compared with placebo has been reported in some meta-analyses and data reviews;26 however, in a long-term, randomized, double-blind, double-dummy, active-controlled trial (Tiotropium Safety and Performance in Respimat [TIOSPIR]) with an observation period of up to 3 years, all-cause mortality was found to be similar in patients receiving tiotropium oral inhalation powder and those receiving tiotropium oral inhalation solution.1,23,26 In addition, no increased risk of death was observed in patients with a history of cardiac disease (including stable cardiac arrhythmias at baseline) receiving tiotropium oral inhalation solution compared with those receiving tiotropium oral inhalation powder.26

Increases in corrected QT (QT_c) interval have been reported in patients receiving tiotropium oral inhalation powder.1 In a multicenter, randomized, double-blind trial in 198 patients with COPD, changes from baseline-corrected QT interval (using either the Bazett or Fridericia corrections) of 30-60 msec occurred in more patients receiving tiotropium compared with those receiving placebo.1 In other clinical trials, an effect of the drug on QT_c intervals was not observed.1 In a crossover, placebo-controlled study of tiotropium oral inhalation powder in healthy individuals, the maximum mean change from baseline in study-specific QT_c compared with placebo was 3.2 or 0.8 msec in patients receiving tiotropium 18 or 54 mcg, respectively.1

Paradoxical Bronchospasm

Acute paradoxical bronchospasm may occur.1,11,23,24 If such a reaction occurs, it should be treated immediately with a short-acting inhaled β₂-adrenergic agonist; tiotropium should be discontinued and alternative therapy considered.1,23,24

Ocular Effects

Tiotropium may worsen angle-closure glaucoma.1,23,24 The drug should be used with caution in patients with angle-closure glaucoma.1,23,24 If signs or symptoms of acute angle-closure glaucoma (e.g., ocular pain or discomfort, blurred vision, visual halos, or colored images in association with conjunctival congestion and corneal edema) occur, patients should consult a clinician immediately.1,23,24 (See Advice to Patients.) Miotic eye drops alone are not considered effective treatment for this condition.1

Temporary blurring of vision or pupillary dilation may occur following inadvertent contact of tiotropium with the eyes.8,11 Care should be taken to avoid contact of the drug with the eyes during oral inhalation.1 (See Advice to Patients.)

Genitourinary Effects

Urinary retention/difficulty or urinary tract infection has been reported with tiotropium therapy.1,23,24 Tiotropium may worsen symptoms and signs of urinary retention (e.g., dysuria); patients should be carefully monitored for such signs and symptoms, especially those with prostatic hyperplasia or bladder neck obstruction.1,11,23,24 A clinician should be consulted immediately if such effects occur.1,23,24 Tiotropium should be used with caution in patients with urinary retention.1,23,24

Accidental Oral Ingestion

Acute intoxication by inadvertent oral ingestion of the dry-powder capsules for oral inhalation is unlikely since tiotropium is not well absorbed systemically.1 Few patients have reported adverse effects following ingestion of the dry-powder capsules.16

Specific Populations

Pregnancy

Category C.1,24 (See Users Guide.)

Limited human data regarding use of orally inhaled tiotropium solution during pregnancy are inadequate to inform a drug-associated risk.23 However, poorly or moderately controlled asthma during pregnancy may increase the maternal risk of preeclampsia and the infant's risk for prematurity, low birth weight, and small size for gestational age.23 The level of asthma control should be closely monitored in pregnant women and therapy adjusted as needed to maintain optimal control.23

Animal studies have not revealed evidence of structural abnormalities at tiotropium dosages of approximately 790 or 8 times the maximum recommended human daily inhalation dosage administered to pregnant rats or rabbits, respectively, during the period of organogenesis.23 However, tiotropium administration resulted in fetal resorption, fetal loss, decreased number of live pups at birth, decreased mean pup weights, and delays in pup sexual maturation in rats receiving approximately 40 times the maximum recommended human daily inhalation dosage.23 In pregnant rabbits, tiotropium administration resulted in increased postimplantation fetal loss at dosages of approximately 430 times the maximum recommended human daily inhalation dosage.23 These adverse fetal effects were not observed at tiotropium dosages approximately 5 or 95 times the maximum recommended human daily inhalation dosage in pregnant rats and rabbits, respectively.23

Lactation

Tiotropium is distributed into milk in rodents.1,23,24 The drug and/or its metabolites are present in milk of lactating rats at concentrations higher than those in plasma.23 It is not known whether tiotropium is distributed into milk in humans.1,23,24 Effects of the drug on breast-fed infants or milk production also are not known.23 The benefits of breast-feeding and the woman's clinical need for tiotropium should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.23 The manufacturer recommends that orally inhaled tiotropium be used with caution in nursing women.1,24

Pediatric Use

Safety and efficacy of orally inhaled tiotropium powder have not been established in children younger than 18 years of age.1,11 Tiotropium oral inhalation powder is not indicated for use in pediatric patients.1

Safety and efficacy of orally inhaled tiotropium solution for the treatment of asthma have been established in pediatric patients 6-17 years of age in several clinical trials up to 1 years' duration.23 In 3 of these trials, 327 adolescents 12-17 years of age with asthma received tiotropium oral inhalation solution at a dosage of 2.5 mcg once daily.23 In 3 additional studies, 345 patients 6-11 years of age with asthma received tiotropium oral inhalation solution at a dosage of 2.5 mcg once daily.23 Safety and efficacy of the drug in these pediatric patients were similar to the effects in patients 18 years of age or older with asthma receiving the drug.23

Safety and efficacy of orally inhaled tiotropium solution have not been established in children younger than 6 years of age.23

Geriatric Use

The frequency of dry mouth, constipation, and urinary tract infection increased with age in clinical trials of tiotropium.1 However, no overall differences in efficacy were observed in geriatric patients relative to younger adults.1,23,24 The manufacturer states that adjustment of tiotropium dosage in geriatric patients is not necessary.1,23,24

Hepatic Impairment

The pharmacokinetics of tiotropium have not been studied in patients with hepatic impairment.1,23,24

Renal Impairment

Since tiotropium is excreted predominantly by the kidneys, the manufacturer recommends that patients with moderate to severe renal impairment (creatinine clearance of less than 60 mL/minute) be monitored closely for anticholinergic effects while receiving tiotropium therapy.1,23,24

Common Adverse Effects

Adverse reactions occurring in at least 3% of patients with COPD receiving tiotropium oral inhalation powder in long-term clinical trials and at a frequency at least 1% greater than with placebo include upper respiratory tract infection,1 dry mouth,1,15 sinusitis,1 pharyngitis,1 urinary tract infection,1 chest pain (nonspecific),1 rhinitis,1 dyspepsia,1 headache,1 abdominal pain,1 edema (dependent),1 arthralgia,1 constipation,1 depression,1 insomnia,1 vomiting,1 infection,1 moniliasis,1 epistaxis,1 myalgia,1 and rash.1

Adverse reactions occurring in more than 3% of patients with COPD receiving tiotropium oral inhalation solution in clinical trials and more frequently than with placebo include pharyngitis,23 cough,23 dry mouth,23 and sinusitis.23

Adverse reactions occurring in more than 2% of patients with asthma receiving tiotropium oral inhalation solution in clinical trials and more frequently than with placebo include pharyngitis,23 headache,23 bronchitis,23 and sinusitis.23

Adverse effects occurring in more than 3% of patients with COPD receiving tiotropium 5 mcg daily in fixed combination with olodaterol 5 mcg daily and more frequently than in patients receiving either drug alone include nasopharyngitis,24 cough,24 and back pain.24

Histamine H2-Antagonists

Pharmacokinetic interaction (increased area under the concentration-time curve [AUC_0-4h], decreased renal clearance of IV tiotropium [not currently available in the US]) with concomitant cimetidine but not ranitidine.1 Pharmacokinetic interactions between tiotropium bromide and histamine H₂-antagonists not considered clinically important.1

Other Drugs

Tiotropium has been used concomitantly with sympathomimetic bronchodilators, methylxanthines, oral or inhaled corticosteroids, antihistamines, mucolytics, leukotriene modifiers, mast-cell stabilizers, and anti-IgE monoclonal antibody therapy without apparent increases in adverse effects.1,23 Use of tiotropium with other anticholinergic drugs (e.g., ipratropium) may cause increased anticholinergic effects, and is therefore not recommended by the manufacturer.1,23

Description

Tiotropium bromide is a nonselective competitive antagonist at muscarinic (M₁-M₅) receptors.1,7,15,23,24 Tiotropium competitively and reversibly inhibits the actions of acetylcholine and other cholinergic stimuli at M₃ receptors in the smooth muscle of the respiratory tract, leading to bronchodilation.1,7,11,15,23,24

Most of a dose of orally inhaled tiotropium powder is swallowed.11 The drug is minimally absorbed into systemic circulation from the GI tract (bioavailability administered as an oral solution is 2-3%);1 the fraction reaching the lungs (about 20%) appears to be readily absorbed.1,7,11 Following administration of the oral inhalation solution, approximately 33% of an inhaled dose reaches the systemic circulation.23 24 In a pharmacokinetic study in patients with chronic obstructive pulmonary disease (COPD), similar systemic exposure was observed following once-daily administration of the oral inhalation powder (18 mcg) or the oral inhalation solution (5 mcg).1,23 In patients with asthma, peak and total systemic exposure of the drug following oral inhalation of the solution is similar between adults and pediatric patients (6-17 years of age).23 Maximum bronchodilator effects may take up to 4-8 weeks of therapy in patients with asthma.23

Following oral inhalation of tiotropium powder in young healthy individuals, approximately 14% of an administered dose is eliminated in urine, principally as unchanged drug.7,8 Urinary excretion of unchanged drug following oral inhalation of tiotropium powder in patients with COPD was 7% over 24 hours.1 Following oral inhalation of tiotropium solution 5 mcg once daily for 21 days in patients with COPD, approximately 19% of the dose was excreted in urine over 24 hours.23 Following administration of tiotropium solution 2.5 mcg in patients with asthma, approximately 13% of an inhaled dose was excreted unchanged in urine over 24 hours.23 Tiotropium is metabolized to a limited extent by the cytochrome P-450 (CYP) microsomal enzyme system, principally by isoenzymes 2D6 and 3A4.1,8,23

Advice to Patients

Provide a copy of the manufacturer's patient information (medication guide) and instructions for use to all patients each time the drug is dispensed.1,23,24 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time the prescription is refilled.1,23,24

Importance of informing a clinician of allergies to any medications prior to initiation of tiotropium bromide therapy.1,24

Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system (HandiHaler^® or Respimat^®).1,16,23,24

Importance of instructing caregivers to assist children with use of the Respimat^® inhalation device.23

Importance of not using the HandiHaler^® or Respimat^® device to administer other drugs.1,11,23,24

Importance of informing a clinician of faulty inhaler performance (i.e., failure to hear or feel capsule vibrate) when certain procedures (i.e., confirming that the mouthpiece is firmly seated in gray base, tapping inhaler gently on a table) do not improve inhaler (Handihaler^®) performance.1

Importance of storing tiotropium dry-powder capsules in sealed blisters and of removing only one capsule immediately before use; unused additional capsules that are exposed to air should be discarded.1

Importance of avoiding contact of the drug with the eyes since this may cause blurred vision and pupillary dilation.1,23,24

Importance of not using tiotropium therapy to relieve acute symptoms or exacerbations of asthma or chronic obstructive pulmonary disease (COPD).1,23,24

Importance of advising patients with asthma that maximum benefits may only be apparent after 4-8 weeks of treatment with tiotropium inhalation solution (Spiriva^® Respimat^®).23

Risk of immediate hypersensitivity reactions such as anaphylaxis, angioedema (e.g., swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching.23 If such signs and/or symptoms occur, tiotropium should be discontinued immediately and a clinician consulted.23

Risk of paradoxical bronchospasm.1,23,24 If paradoxical bronchospasm occurs, tiotropium should be discontinued.1,23,24

Risk of worsening of angle-closure glaucoma.1,23,24 Importance of immediately informing a clinician if eye pain or discomfort, blurred vision, or visual halos or colored images in association with conjunctival congestion or corneal edema occur.1,23,24

Importance of advising patients to use caution when engaging in activities (e.g., driving a vehicle, operating appliances or machinery) since the drug may cause dizziness or blurred vision.1,23,24

Risk of worsening of urinary retention.1,23,24 Importance of immediately informing a clinician if symptoms of urinary retention (e.g., dysuria) occur.1,23,24

Importance of keeping drug out of reach of children.1

Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs (e.g., eye drops) and herbal supplements, as well as any concomitant illnesses (e.g., urinary difficulty, enlarged prostate, narrow angle glaucoma).1,11,23,24

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,23,24

Importance of informing patients of other important precautionary information.1,23,24 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Boehringer Ingelheim. Spiriva^® HandiHaler^® (tiotropium bromide) inhalation powder prescribing information. Ridgefield, CT; 2016 Jan.

2. Veterans' Health Administration Department of Veteran Affairs. The pharmacologic management of chronic obstructive pulmonary disease. Washington, DC: Veterans' Health Administration; 1999 June. Pharmacy Benefits Management No. 99-0012. Accessed Sep. 30, 2002. [Web]

3. Veterans' Health Administration, Department of Veterans' Affairs. VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease: complete summary. Washington, DC: Veterans' Health Administration; 1999 Aug.

4. Vincken W, van Noord JA, Greefhorst AP et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J . 2002; 19:209-16. [PubMed 11871363]

6. Casaburi R, Mahler DA, Jones PW et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructuve pulmonary disease. Eur Respir J . 2002; 19:217-24. [PubMed 11866001]

7. Hvizdos KM, Goa KL. Tiotropium bromide. Drugs . 2002; 62:1195-203. [PubMed 12010082]

8. . Tiotropium (Spiriva) for COPD. Med Lett Drugs Ther . 2004; 46:41-2. [PubMed 15159658]

9. Brusasco V, Hodder R, Miravitlles M et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax . 2003; 58:399-404. [PubMed 12728159][PubMedCentral]

10. Donohue JF, van Noord JA, Bateman ED et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest . 2002; 122:47-55. [PubMed 12114338]

11. Boehringer Ingelheim, Ridgefield, CT: Personal communication.

12. ATS/ERS Standards for the diagnosis and management of patients with COPD. New York, NY: American Thoracic Society, European Respiratory Society; 2004. Available from website. Accessed Dec. 8, 2004. [Web]

13. O'Donnell DE, Aaron S, Bourbeau J et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease-2003. Can Respir J . 2003; 10(Suppl. A):11A-65A. [PubMed 12861361]

14. Celli BR, Macnee W. Standard for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J . 2004; 23:932-46. [PubMed 15219010]

15. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease, World Health Organization; 2007 Dec. Available at:[Web]. Accessed 2008 May 19..

16. Food and Drug Administration. FDA public health advisory: Important information on correct use of Spiriva and Foradil capsules. Rockville, MD; 2008 Feb 29. Available at [Web]

18. Qaseem A, Snow V, Shekelle P et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med . 2007; 147:633-8. [PubMed 17975186]

19. Food and Drug Administration. Early communication about an ongoing safety review of tiotropium (marketed as Spiriva HandiHaler). Rockville, MD; 2008 Oct 7. Available at [Web]. Accessed 2008 Oct 8.

20. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA . 2008; 300:1439-50. [PubMed 18812535]

21. Lee TA, Pickard AS, Au DH et al. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med . 2008; 149:380-90. [PubMed 18794557]

23. Boehringer Ingelheim. Spiriva^® Respimat^® (tiotropium bromide) inhalation spray prescribing information. Ridgefield, CT; 2017 Feb.

24. Boehringer Ingelheim. Stiolto^® Respimat^® (tiotropium bromide and olodaterol) inhalation spray prescribing information. Ridgefield, CT; 2016 Jun.

25. Buhl R, Maltais F, Abrahams R et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J . 2015; 45:969-79. [PubMed 25573406][PubMedCentral]

26. Wise RA, Anzueto A, Cotton D et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med . 2013; 369:1491-501. [PubMed 23992515]

27. Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med . 2008; 359:1543-54. [PubMed 18836213]

28. Food and Drug Administration. Follow-up to the October 2008 updated early communication about an ongoing safety review of tiotropium (marketed as Spiriva HandiHaler). Rockville, MD; 2010 Jan 24. Accessed 2017 Jan 7. [Web]