VA Class: RE105
Chemical Name: di-2-thienylglycolate-6β,7β-Epoxy-3β-hydroxy-8-methyl-1αH,5αH-tropanium bromide
Molecular Formula: C19H22BrNO4S2
CAS Number: 139404-48-1
Brands: Spiriva Handihaler
Bronchodilator; a synthetic quaternary ammonium antimuscarinic agent.1
Uses for Tiotropium Bromide
Long-term treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema.1 12 13 14 15
A long-acting bronchodilator (e.g., orally inhaled salmeterol, formoterol, tiotropium) or an inhaled corticosteroid recommended for maintenance monotherapy in patients with moderate to severe COPD (e.g., FEV1 30 to <80% of predicted15 or, alternatively, <60% of predicted)18 who have persistent symptoms not relieved by as-needed therapy with a selective, short-acting inhaled β2-adrenergic agonist.15 18 Maintenance therapy with long-acting bronchodilators in such patients more effective and more convenient than regular therapy with short-acting bronchodilators.13 15 18 Insufficient data to favor one maintenance monotherapy over another in patients with moderate to severe COPD.15 18 In selected patients with inadequate response, may use a combination of several long-acting bronchodilators, such as tiotropium, and a long-acting β2-adrenergic agonist.13 15
In patients with severe to very severe COPD (e.g., FEV1 <30 to <50% of predicted), some clinicians recommend addition of an inhaled corticosteroid to one or more long-acting bronchodilators, given separately or in fixed combination;12 14 15 however, benefits of combination therapy over monotherapy not consistently established.15 18 If inadequate response or limiting adverse effects occur, may consider the addition or substitution of extended-release oral theophylline.12 14 15
Not indicated for the initial treatment of acute episodes of bronchospasm or acute exacerbations of COPD;1 5 a drug with a more rapid onset of action (e.g., a short-acting β-adrenergic agonist) preferred.2 3 7 8
Tiotropium Bromide Dosage and Administration
Administer by oral inhalation only using a special oral inhalation device (HandiHaler) that delivers powdered drug from capsules.1 5
Do not take capsules orally, as intended effects on the lungs will not be obtained.1 5 16
Open the dust cap by pressing the green piercing button.5 Pull the dust cap upward on the side opposite the hinge of the Handihaler device to expose the mouthpiece.5 Open the mouthpiece by pulling the mouthpiece ridge upward on the side opposite the hinge of the inhaler to expose the center chamber.5 Carefully open the blister card to expose only one capsule immediately before use.1 5 Place capsule into the center chamber of the inhaler,1 5 and close the inhaler mouthpiece firmly until it snaps (clicks) into position, leaving the dust cap open (up).5 (See Stability.) Push down on the mouthpiece ridge to make sure that the mouthpiece is seated in the gray base of the inhaler.5 Hold the inhaler with the seated mouthpiece upward, depress the green button on the side of the inhaler completely (until the button is flush with the gray base of the inhaler), then release the button.1 5 The green button pierces the capsule and disperses the powdered drug upon inspiration.1 5 11 Do not press the green piercing button more than once.5 11
Exhale completely; do not exhale into the HandiHaler device.5 Hold the inhaler by the gray base; take care not to block the air intake vents near the mouthpiece ridge.5 With the head kept level, place the mouthpiece of the inhaler between the lips (inhaler is in a horizontal position) and inhale deeply and slowly through the inhaler with a rate sufficient to hear or feel the loaded capsule vibrate.5 11 Pressure from inhalation will disperse the drug from center chamber into air stream created by the patient’s inhalation.1 5 Continue breathing until the lungs are full.5 Remove the inhaler from the mouth and hold the breath for as long as comfortable, then resume normal breathing.5 Breathe out completely and inhale once again to ensure full delivery of the powder.5 Do not press the green piercing button again.5 Upon completion of the second inhalation, open the mouthpiece and tip the device to dispose of the used capsule; close the mouthpiece and dust cap of the inhaler device.5
Do not take extra doses despite not being able to hear or feel the capsule vibrate.5 Tap the inhaler device on a table, holding the gray base in an upright position.5 Then check to see that the mouthpiece is properly seated in the gray base and attempt to inhale through the device again.5 (See Advice to Patients.)
If no improvement in COPD symptoms, make sure patient is inhaling the drug using the oral inhaler rather than swallowing the dry-powder capsules.16 (See Accidental Oral Ingestion under Cautions.)
Clean the Handihaler device once a month.5 Open the dust cap and mouthpiece, then open the base by lifting the green piercing button; rinse with warm water (do not use cleaning agents or detergents) to remove any remaining powder.5 Dry the inhaler thoroughly; leave dust cap, mouthpiece, and gray base open to air dry for 24 hours.5 Do not use the inhaler when wet.5 If needed, clean the outside of the mouthpiece with a moist, but not wet, tissue.5 11
Available as tiotropium bromide monohydrate; dosage expressed in terms of anhydrous tiotropium.1 11
Each capsule contains 18 mcg of tiotropium as an inhalation powder.1 However, the precise amount of drug delivered to the lungs depends on factors such as the patient’s inspiratory flow.1
18 mcg (contents of one capsule) once daily.1 11
No dosage adjustments required.1
No dosage adjustments required.1
No dosage adjustments required.1
Cautions for Tiotropium Bromide
Known hypersensitivity to tiotropium bromide or any ingredient in the formulation.1
Known hypersensitivity to atropine or its derivatives (e.g., ipratropium).1
Delayed onset of action; not indicated for initial treatment.1 5 Do not use for the treatment of acute episodes of bronchospasm (i.e., as rescue therapy).1 5
Possible Increased Risk of Stroke, Mortality, and/or Cardiovascular Events
Data are conflicting; possible increased risk of stroke identified from ongoing safety monitoring and pooled analysis of placebo-controlled trials.19 Data on approximately 13,500 patients with COPD suggest an absolute excess risk of 2 strokes per 1000 patient-years with exposure to tiotropium compared with that of placebo.19 Other observational data involving over 32,000 patients and pooled analyses of almost 15,000 patients suggest an increased risk of mortality and/or cardiovascular events with use of inhaled anticholinergic agents, including tiotropium bromide.20 21 However, increased risk of stroke with tiotropium not revealed in a preliminary analysis of a placebo-controlled trial (Understanding the Potential Long-term Impacts on Function with Tiotropium [UPLIFT]) in approximately 6000 patients with COPD.19 Results of these analyses pending confirmation by FDA; postmarketing adverse event reports and results of the UPLIFT trial currently under review.19
Immediate hypersensitivity reactions, including angioedema, reported.5 Possible acute paradoxical bronchospasm.1 11 If such reactions occur, discontinue immediately and consider alternative therapy.1
Possible temporary blurred vision, worsening 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), or pupillary dilation following inadvertent contact of tiotropium with the eyes.1 5 8 11 Miotic eye drops alone are not considered effective treatment for this condition.1 (See Advice to Patients.)
Possible urinary retention, urinary difficulty,1 or urinary tract infection.1
May worsen symptoms and signs associated with prostatic hyperplasia or bladder neck obstruction.1 11 Use with caution in patients with these conditions.1
Accidental Oral Ingestion
Acute intoxication unlikely following inadvertent oral ingestion of the dry-powder capsules for oral inhalation since the drug is not well absorbed systemically.1 Adverse effect reports uncommon following ingestion of dry-powder capsules.16
Distributed into milk in rodents; not known whether tiotropium is distributed into human milk.1 Use caution.1
Safety and efficacy not established in children <18 years of age.1 11
Possible increased incidence of dry mouth, constipation, and urinary tract infection compared with younger adults.1 However, no overall differences in efficacy relative to younger adults.1
Pharmacokinetics not evaluated, but impact of hepatic impairment should be minimal.1
Clearance may be decreased; closely monitor patients with moderate to severe renal impairment (CLcr of ≤50 mL/minute) during therapy.1
Common Adverse Effects
Upper respiratory tract infection,1 dry mouth,1 accidents,1 sinusitis,1 pharyngitis,1 urinary tract infection,1 chest pain (nonspecific),1 rhinitis,1 dyspepsia,1 abdominal pain,1 edema (dependent),1 constipation,1 vomiting,1 infection,1 moniliasis,1 epistaxis,1 myalgia,1 rash.1
Interactions for Tiotropium Bromide
Metabolized by CYP isoenzymes, principally CYP2D6 and CYP3A4.1 8
Does not inhibit CYP1A1, 1A2, 2B6, C29, 2C19, 2D6, 2E1, or 3A4.1
No adverse drug interactions reported1
Interaction not studied1
Concomitant use not recommended by manufacturer1
Corticosteroids, oral and inhaled
No adverse drug interactions reported1
Histamine H2-receptor antagonists
Increased AUC and decreased renal clearance of IV tiotropium (not currently available in the US) with concomitant cimetidine but not ranitidine1
Pharmacokinetic interactions not considered clinically important1
No adverse drug interactions reported1
Tiotropium Bromide Pharmacokinetics
Following inhalation, absolute bioavailability is 19.5%.1 Most of a dose is swallowed1 11 and minimally absorbed into systemic circulation;1 the fraction reaching the lungs appears to be readily absorbed.1 7 11 Peak plasma concentrations following oral inhalation are attained within 5 minutes.1
Following oral inhalation, bronchodilation evident within 30 minutes.4
Bronchodilation generally persists for >24 hours.1
Food does not appear to affect absorption from GI tract.1
In patients with renal impairment, increased plasma drug concentrations and AUC.1
Widely distributed into tissues.1 Does not penetrate the blood-brain barrier in animals.1
Plasma Protein Binding
Metabolized to a limited extent, principally by isoenzymes CYP2D6 and 3A4.1 8
Excreted principally in the feces (86%), mainly as unabsorbed drug, and in the urine (approximately 14%) as unchanged drug.1 7 8
Terminal elimination half-life is 5–6 days following oral inhalation.1
In patients with renal impairment, reduced clearance.1
Powder for Oral Inhalation
25°C (may be exposed to 15–30°C).1 Do not expose to extreme temperatures and moisture.1
Keep capsules in sealed blisters until immediately before use.1 5 Do not store used or unused capsules in the inhaler device.5 Remove only one capsule immediately before use or effectiveness of the drug may be reduced.1 5 Discard additional capsules if opened and exposed to air (i.e., not intended for immediate use).1 5 11
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
Advice to Patients
Importance of providing patient a copy of manufacturer’s patient information.5
Importance of informing a clinician of allergies to any medications prior to initiation of tiotropium bromide therapy.5
Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system (HandiHaler).1 5 16
Importance of not using the HandiHaler device to administer other drugs.5 11
Importance of consulting a clinician of faulty inhaler performance (i.e., if capsule vibration is not felt or heard upon inhalation) when certain procedures (i.e., confirming that the mouthpiece is firmly seated in the gray base, tapping the inhaler gently on a table) do not improve inhaler performance.5
Importance of avoiding inadvertent contact of the drug with the eyes, as contact may cause blurred vision and pupillary dilation.1 5
Importance of not using tiotropium to relieve acute symptoms or exacerbations of COPD.1 5
Importance of patients consulting clinician before discontinuing tiotropium therapy if they are concerned about potential adverse effects (e.g., stroke).19
Importance of 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
Importance of informing clinicians of existing or contemplated concomitant 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, angle-closure glaucoma).1 5 11
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 5
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Powder for Inhalation (contained in capsules)
18 mcg (of anhydrous tiotropium)
Boehringer Ingelheim (comarketed by Pfizer)
AHFS DI Essentials. © Copyright 2017, Selected Revisions August 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
1. Boehringer Ingelheim. Spiriva HandiHaler (tiotropium bromide) inhalation powder prescribing information. Ridgefield, CT; 2007 Dec.
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. Available at . Accessed Sep. 30, 2002.
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]
5. Boehringer Ingelheim. Spiriva HandiHaler (tiotropium bromide) inhalation powder patient instructions for use. Ridgefield, CT; 2007 Dec.
6. Casaburi R, Mahler DA, Jones PW et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive 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. Anon. Tiotropium (Spiriva) for COPD. Med Lett Drugs Ther. 2004: 46:41-2.
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.
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.
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.
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.
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 from website. 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 from website. Accessed 2008 Apr 23.
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 from website. 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. JAMA. 2008; 300:1439-50. [PubMed 18812535]
21. Lee TA, Pickard AS, Au DH et al. Risk of death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008; 149:380-90. [PubMed 18794557]
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