Drug Detail:Spiriva (Tiotropium inhalation [ tye-oh-troe-pee-um ])
Drug Class: Anticholinergic bronchodilators
Highlights of Prescribing Information
SPIRIVA® HANDIHALER® (tiotropium bromide inhalation powder), for oral inhalation use
Initial U.S. Approval: 2004
Indications and Usage for Spiriva
SPIRIVA HANDIHALER is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations (1)
Spiriva Dosage and Administration
- For oral inhalation only. DO NOT swallow SPIRIVA capsules. Only use SPIRIVA capsules with the HANDIHALER device (2)
- Two inhalations of the powder contents of a single SPIRIVA capsule (18 mcg) once daily (2)
Dosage Forms and Strengths
Inhalation powder: SPIRIVA capsules contain 18 mcg tiotropium powder for use with HANDIHALER device (3)
Contraindications
Hypersensitivity to tiotropium, ipratropium, or any components of SPIRIVA capsules (4)
Warnings and Precautions
- Not for acute use: Not a rescue medication (5.1)
- Immediate hypersensitivity reactions: Discontinue SPIRIVA HANDIHALER at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. Use with caution in patients with severe hypersensitivity to milk proteins. (5.2)
- Paradoxical bronchospasm: Discontinue SPIRIVA HANDIHALER and consider other treatments if paradoxical bronchospasm occurs (5.3)
- Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4)
- Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (5.5)
Adverse Reactions/Side Effects
The most common adverse reactions (>5% incidence in the 1-year placebo-controlled trials) were upper respiratory tract infection, dry mouth, sinusitis, pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, and rhinitis (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA HANDIHALER with other anticholinergic-containing drugs. (7.2)
Use In Specific Populations
Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects (2, 8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2021
Full Prescribing Information
1. Indications and Usage for Spiriva
SPIRIVA HANDIHALER (tiotropium bromide inhalation powder) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA HANDIHALER is indicated to reduce exacerbations in COPD patients.
2. Spiriva Dosage and Administration
For oral inhalation only. Do not swallow SPIRIVA capsules, as the intended effects on the lungs will not be obtained. The contents of the SPIRIVA capsules should only be used with the HANDIHALER device [see Overdosage (10)].
The recommended dose of SPIRIVA HANDIHALER is two inhalations of the powder contents of one SPIRIVA capsule, once-daily, with the HANDIHALER device [see Patient Counseling Information (17)]. Do not take more than one dose in 24 hours.
For administration of SPIRIVA HANDIHALER, a SPIRIVA capsule is placed into the center chamber of the HANDIHALER device. The SPIRIVA capsule is pierced by pressing and releasing the green piercing button on the side of the HANDIHALER device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [see Patient Counseling Information (17)].
No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given SPIRIVA HANDIHALER should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].
3. Dosage Forms and Strengths
Inhalation Powder: SPIRIVA HANDIHALER consists of SPIRIVA capsules containing tiotropium powder for oral inhalation and a HANDIHALER device. SPIRIVA capsules contain 18 mcg of tiotropium in a light green, hard gelatin capsule with "TI 01" printed on one side and Boehringer Ingelheim company logo on the other side. The HANDIHALER device is only intended for use with the SPIRIVA capsules.
4. Contraindications
SPIRIVA HANDIHALER is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product [see Warnings and Precautions (5.2)]. In clinical trials and postmarketing experience with SPIRIVA HANDIHALER, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)].
5. Warnings and Precautions
5.1 Not for Acute Use
SPIRIVA HANDIHALER is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.
5.2 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 SPIRIVA HANDIHALER. If such a reaction occurs, therapy with SPIRIVA HANDIHALER 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 SPIRIVA HANDIHALER. In addition, SPIRIVA HANDIHALER should be used with caution in patients with severe hypersensitivity to milk proteins.
5.3 Paradoxical Bronchospasm
Inhaled medicines, including SPIRIVA HANDIHALER, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with SPIRIVA HANDIHALER should be stopped and other treatments considered.
5.4 Worsening of Narrow-Angle Glaucoma
SPIRIVA HANDIHALER 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.
5.5 Worsening of Urinary Retention
SPIRIVA HANDIHALER should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (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.
6. Adverse Reactions/Side Effects
The following adverse reactions are described, or described in greater detail, in other sections:
- Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)]
- Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
- Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)]
- Worsening of urinary retention [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
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.
6.2 Postmarketing Experience
Adverse reactions have been identified during worldwide post-approval use of SPIRIVA HANDIHALER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.
7. Drug Interactions
7.1 Sympathomimetics, Methylxanthines, Steroids
SPIRIVA HANDIHALER 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.
7.2 Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA HANDIHALER with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].
8. Use In Specific Populations
8.4 Pediatric Use
SPIRIVA HANDIHALER is not indicated for use in children. The safety and effectiveness of SPIRIVA HANDIHALER in pediatric patients have not been established.
8.5 Geriatric Use
Based on available data, no adjustment of SPIRIVA HANDIHALER dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
Of the total number of patients who received SPIRIVA HANDIHALER in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the SPIRIVA HANDIHALER and the comparator groups for most events. Dry mouth increased with age in the SPIRIVA HANDIHALER group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the SPIRIVA HANDIHALER group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups.
8.6 Renal Impairment
Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA HANDIHALER should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].
10. Overdosage
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.
Treatment of overdosage consists of discontinuation of SPIRIVA HANDIHALER together with institution of appropriate symptomatic and/or supportive therapy.
11. Spiriva Description
SPIRIVA HANDIHALER consists of SPIRIVA capsules and a HANDIHALER device. Each light green, hard gelatin SPIRIVA capsule contains a dry powder consisting of 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins).
The contents of SPIRIVA capsules are intended for oral inhalation only, and are intended for administration only with the HANDIHALER device.
The active component of SPIRIVA HANDIHALER is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]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 HANDIHALER device is an inhalation device used to inhale the dry powder contained in the SPIRIVA capsule. The dry powder is delivered from the HANDIHALER device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HANDIHALER device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HANDIHALER device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HANDIHALER device, which may vary from patient to patient, and may vary with the exposure time of the SPIRIVA capsule outside the blister pack.
12. Spiriva - Clinical Pharmacology
12.1 Mechanism of Action
Tiotropium is a long-acting, antimuscarinic agent, 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.
12.3 Pharmacokinetics
Tiotropium is administered by dry powder inhalation. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the HANDIHALER device resulted in a similar systemic exposure between the two products.
13. Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 (MRHDID) 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 assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay.
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 40 times the MRHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m2 basis).
14. Clinical Studies
The SPIRIVA HANDIHALER (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2663 patients with COPD (1308 receiving SPIRIVA HANDIHALER): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7.
In these studies, SPIRIVA HANDIHALER, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose.
Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial.
16. How is Spiriva supplied
SPIRIVA HANDIHALER consists of SPIRIVA capsules and the HANDIHALER device. SPIRIVA capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the SPIRIVA capsule cap and "TI 01" on the SPIRIVA capsule body, or vice versa.
The HANDIHALER device is gray colored with a green piercing button. It is imprinted with SPIRIVA HANDIHALER (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo. It is also imprinted to indicate that SPIRIVA capsules should not be stored in the HANDIHALER device and that the HANDIHALER device is only to be used with SPIRIVA capsules.
SPIRIVA capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. SPIRIVA capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual SPIRIVA capsule is opened.
The following packages are available:
- carton containing 5 SPIRIVA capsules (1 unit-dose blister card) and 1 HANDIHALER inhalation device (NDC 0597-0075-75) (institutional pack)
- carton containing 30 SPIRIVA capsules (3 unit-dose blister cards) and 1 HANDIHALER inhalation device (NDC 0597-0075-41)
- carton containing 90 SPIRIVA capsules (9 unit-dose blister cards) and 1 HANDIHALER inhalation device (NDC 0597-0075-47)
Keep out of reach of children. Do not get powder into eyes.
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Instructions for Use
SPIRIVA® (speh REE vah) HANDIHALER®
(tiotropium bromide inhalation powder)
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| Do not swallow SPIRIVA capsules. |
Important Information about using your SPIRIVA HANDIHALER
- Do not swallow SPIRIVA capsules.
- SPIRIVA capsules should only be used with the HANDIHALER device and inhaled through your mouth (oral inhalation).
- Do not use your HANDIHALER device to take any other medicine.
First read the Patient Information, then read these Instructions for Use before you start to use SPIRIVA HANDIHALER and each time you refill your prescription. There may be new information.
Becoming familiar with your HANDIHALER device and SPIRIVA capsules:
Your SPIRIVA HANDIHALER comes with SPIRIVA capsules in blister packaging and a HANDIHALER device. Use the new HANDIHALER device provided with your medicine.
| The parts of your HANDIHALER device include:
(See Figure A)
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Each SPIRIVA capsule is packaged in a blister. (See Figure B) |
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Taking your full daily dose of medicine requires 4 main steps.
Step 1. Opening your HANDIHALER device:
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After removing your HANDIHALER device from the pouch:
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Step 2. Inserting the SPIRIVA capsule into your HANDIHALER device:
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Each day, separate only 1 of the blisters from the blister card by tearing along the perforated line. (See Figure G) |
Remove the SPIRIVA capsule from the blister:
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Place the SPIRIVA capsule in the center chamber of your HANDIHALER device. (See Figure I) |
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Close the mouthpiece firmly against the gray base until you hear a click. Leave the dust cap (lid) open. (See Figure J) |
Step 3. Piercing the SPIRIVA capsule:
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Step 4. Taking your full daily dose (2 inhalations from the same SPIRIVA capsule):
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Breathe out completely in 1 breath, emptying your lungs of any air. (See Figure L) Important: Do not breathe into your HANDIHALER device. |
With your next breath, take your medicine:
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To get your full daily dose, you must again, breathe out completely (See Figure N) and for a second time, breathe in (See Figure O) from the same SPIRIVA capsule. Important: Do not press the green piercing button again. |
| Remember: To get your full medicine dose each day, you must breathe in 2 times from the same SPIRIVA capsule. Make sure you breathe out completely each time before you breathe in from your HANDIHALER device. |
Caring for and storing your SPIRIVA HANDIHALER:
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If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine:
| Do not press the green piercing button again. Hold your HANDIHALER device with the mouthpiece pointed up and tap your HANDIHALER device gently on a table. (See Figure Q) Check to see that the mouthpiece is completely closed. Breathe out completely before deeply breathing in again with the mouthpiece in your mouth. (See Figure O) If you still do not hear or feel the SPIRIVA capsule rattle after repeating the above steps:
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Cleaning your HANDIHALER device:
Clean your HANDIHALER device as needed. (See Figure R)
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Helpful Hints to help ensure that you are properly taking your full daily dose of SPIRIVA HANDIHALER:
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For current prescribing information for SPIRIVA HANDIHALER, scan the code or for additional information you may also call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
SPIRIVA® and HANDIHALER® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH.
Copyright © 2021 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
Revised: November 2021
COL10494AK082021
| SPIRIVA
HANDIHALER
tiotropium bromide capsule |
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| Labeler - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944) |
| Registrant - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Boehringer Ingelheim Pharma GmbH and Co. KG | 551147440 | ANALYSIS(0597-0075) , API MANUFACTURE(0597-0075) , LABEL(0597-0075) , MANUFACTURE(0597-0075) , PACK(0597-0075) | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| West-Ward Columbus Inc. | 058839929 | LABEL(0597-0075) , PACK(0597-0075) | |
