These Highlights Do Not Include All The Information Needed To Use Spiriva Handihaler Safely And Effectively. See Full Prescribing Information For Spiriva Handihaler.

SPIRIVA^® (speh REE vah) HANDIHALER^®

(tiotropium bromide inhalation powder)

Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the HANDIHALER device and inhaled through your mouth (oral inhalation).

Read the information that comes with your SPIRIVA HANDIHALER before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is SPIRIVA HANDIHALER?

• SPIRIVA HANDIHALER is a prescription medicine used each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
• SPIRIVA HANDIHALER helps make your lungs work better for 24 hours. SPIRIVA HANDIHALER relaxes your airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. SPIRIVA HANDIHALER works best and may help make it easier to breathe when you use it every day.
• SPIRIVA HANDIHALER reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.

SPIRIVA HANDIHALER is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems.

It is not known if SPIRIVA HANDIHALER is safe and effective in children.

Who should not take SPIRIVA HANDIHALER?

Do not use SPIRIVA HANDIHALER if you:

• are allergic to tiotropium, ipratropium (Atrovent^®), or any of the ingredients in SPIRIVA HANDIHALER. See the end of this leaflet for a complete list of ingredients in SPIRIVA HANDIHALER.

Symptoms of a serious allergic reaction to SPIRIVA HANDIHALER may include:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

What should I tell my doctor before using SPIRIVA HANDIHALER?

Before taking SPIRIVA HANDIHALER, tell your doctor about all your medical conditions, including if you:

• have kidney problems.
• have glaucoma. SPIRIVA HANDIHALER may make your glaucoma worse.
• have an enlarged prostate, problems passing urine, or a blockage in your bladder. SPIRIVA HANDIHALER may make these problems worse.
• are pregnant or plan to become pregnant. It is not known if SPIRIVA HANDIHALER could harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not known if SPIRIVA HANDIHALER passes into breast milk. You and your doctor will decide if SPIRIVA HANDIHALER is right for you while you breast-feed.
• have a severe allergy to milk proteins. Ask your doctor if you are not sure.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way SPIRIVA HANDIHALER works. SPIRIVA HANDIHALER is an anticholinergic medicine. You should not take other anticholinergic medicines while using SPIRIVA HANDIHALER, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

How should I take SPIRIVA HANDIHALER?

• Use SPIRIVA HANDIHALER exactly as prescribed. Use SPIRIVA HANDIHALER one time every day.
• Read the "Instructions for Use" at the end of this leaflet before you use SPIRIVA HANDIHALER. Talk with your doctor if you do not understand the instructions.
• Do not swallow SPIRIVA capsules.
• Only use SPIRIVA capsules with the HANDIHALER device.
• Do not use the HANDIHALER device to take any other medicine.
• SPIRIVA HANDIHALER comes as a powder in a SPIRIVA capsule that fits the HANDIHALER device. Each SPIRIVA capsule, containing only a small amount of SPIRIVA powder, is one full dose of medicine.
• Separate one blister from the blister card. Then take out one of the SPIRIVA capsules from the blister package right before you use it.
• After the capsule is pierced, take a complete dose of SPIRIVA HANDIHALER by breathing in the powder by mouth two times, using the HANDIHALER device (take 2 inhalations from one SPIRIVA capsule). See the " Instructions for Use " at the end of this leaflet.
• Throw away any SPIRIVA capsule that is not used right away after it is taken out of the blister package. Do not leave the SPIRIVA capsules open to air; they may not work as well.
• If you miss a dose, take it as soon as you remember. Do not use SPIRIVA HANDIHALER more than one time every 24 hours.
• If you use more than your prescribed dose of SPIRIVA HANDIHALER, call your doctor or a poison control center.

What should I avoid while using SPIRIVA HANDIHALER?

• Do not let the powder from the SPIRIVA capsule get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.
• SPIRIVA HANDIHALER can cause dizziness and blurred vision. Should you experience these symptoms you should use caution when engaging in activities such as driving a car or operating appliances or other machines.

What are the possible side effects of SPIRIVA HANDIHALER?

SPIRIVA HANDIHALER can cause serious side effects, including: Allergic reaction. Symptoms may include:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

• Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.

If you have these symptoms of bronchospasm, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

• New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:
  • eye pain
  • blurred vision
  • seeing halos (visual halos) or colored images along with red eyes

Using only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking SPIRIVA HANDIHALER and call your doctor right away.

• New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination.

If you have these symptoms of urinary retention, stop taking SPIRIVA HANDIHALER and call your doctor right away.

Other side effects with SPIRIVA HANDIHALER include:

• upper respiratory tract infection
• dry mouth
• sinus infection
• sore throat
• non-specific chest pain
• urinary tract infection
• indigestion
• runny nose
• constipation
• increased heart rate
• blurred vision

These are not all the possible side effects with SPIRIVA HANDIHALER. Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store SPIRIVA HANDIHALER?

• Do not store SPIRIVA capsules in the HANDIHALER device.
• Store SPIRIVA capsules in the sealed blister package at room temperature 68°F to 77°F (20°C to 25°C).
• Keep SPIRIVA capsules away from heat and cold (do not freeze).
• Store SPIRIVA capsules in a dry place. Throw away any unused SPIRIVA capsules that have been open to air.

Ask your doctor or pharmacist if you have any questions about storing your SPIRIVA capsules.

Keep SPIRIVA HANDIHALER, SPIRIVA capsules, and all medicines out of the reach of children.

General information about SPIRIVA HANDIHALER

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use SPIRIVA HANDIHALER for a purpose for which it has not been prescribed. Do not give SPIRIVA HANDIHALER to other people even if they have the same symptoms that you have. It may harm them.

For more information about SPIRIVA HANDIHALER, talk with your doctor. You can ask your doctor or pharmacist for information about SPIRIVA HANDIHALER that is written for health professionals.

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.

What are the ingredients in SPIRIVA HANDIHALER?

Active ingredient: tiotropium

Inactive ingredient: lactose monohydrate

What is COPD (Chronic Obstructive Pulmonary Disease)?

COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to breathe.

This Patient Information 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

6-Month to 1-Year Trials

The data described below reflect exposure to SPIRIVA HANDIHALER in 2663 patients. SPIRIVA HANDIHALER was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with SPIRIVA HANDIHALER at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV ₁ ) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected.

The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.

Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated SPIRIVA HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the SPIRIVA HANDIHALER group in the 1-year placebo-controlled trials where the rates in the SPIRIVA HANDIHALER group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA HANDIHALER treatment group, but were <1% in excess of the placebo group.

Other reactions that occurred in the SPIRIVA HANDIHALER group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.

In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Specific Populations (8.5)].

Two multicenter, 6-month, controlled studies evaluated SPIRIVA HANDIHALER in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.

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.

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[3.3.1.0^2,4]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.

SPIRIVA HANDIHALER is not indicated for use in children. The safety and effectiveness of SPIRIVA HANDIHALER in pediatric patients have not been established.

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.

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.

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)].

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)]

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA HANDIHALER with other anticholinergic-containing drugs. (7.2)

As a predominantly renally excreted drug, 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 Clinical Pharmacology (12.3)].

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)].

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)].

SPIRIVA® (speh REE vah) HANDIHALER®

(tiotropium bromide inhalation powder)

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.

Taking your full daily dose of medicine requires 4 main steps.

Step 1. Opening your HANDIHALER device:

Step 2. Inserting the SPIRIVA capsule into your HANDIHALER device:

Step 3. Piercing the SPIRIVA capsule:

Step 4. Taking your full daily dose (2 inhalations from the same SPIRIVA capsule):

Caring for and storing your SPIRIVA HANDIHALER:

If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine:

Cleaning your HANDIHALER device:

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

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.

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.

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

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.

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.

• 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)

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)].

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.

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.

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.

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects (2, 8.6)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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.

Product: 50090-4248

NDC: 50090-4248-0 10 CAPSULE in a BLISTER PACK / 3 in a CARTON

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.

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.

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.

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).

6-Month to 1-Year Trials

The data described below reflect exposure to SPIRIVA HANDIHALER in 2663 patients. SPIRIVA HANDIHALER was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with SPIRIVA HANDIHALER at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV ₁ ) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected.

The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.

Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated SPIRIVA HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the SPIRIVA HANDIHALER group in the 1-year placebo-controlled trials where the rates in the SPIRIVA HANDIHALER group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA HANDIHALER treatment group, but were <1% in excess of the placebo group.

Other reactions that occurred in the SPIRIVA HANDIHALER group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.

In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Specific Populations (8.5)].

Two multicenter, 6-month, controlled studies evaluated SPIRIVA HANDIHALER in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.

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.

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[3.3.1.0^2,4]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.

SPIRIVA HANDIHALER is not indicated for use in children. The safety and effectiveness of SPIRIVA HANDIHALER in pediatric patients have not been established.

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.

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.

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)].

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)]

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SPIRIVA HANDIHALER with other anticholinergic-containing drugs. (7.2)

SPIRIVA^® (speh REE vah) HANDIHALER^®

(tiotropium bromide inhalation powder)

Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the HANDIHALER device and inhaled through your mouth (oral inhalation).

Read the information that comes with your SPIRIVA HANDIHALER before you start using it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is SPIRIVA HANDIHALER?

• SPIRIVA HANDIHALER is a prescription medicine used each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
• SPIRIVA HANDIHALER helps make your lungs work better for 24 hours. SPIRIVA HANDIHALER relaxes your airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. SPIRIVA HANDIHALER works best and may help make it easier to breathe when you use it every day.
• SPIRIVA HANDIHALER reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.

SPIRIVA HANDIHALER is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems.

It is not known if SPIRIVA HANDIHALER is safe and effective in children.

Who should not take SPIRIVA HANDIHALER?

Do not use SPIRIVA HANDIHALER if you:

• are allergic to tiotropium, ipratropium (Atrovent^®), or any of the ingredients in SPIRIVA HANDIHALER. See the end of this leaflet for a complete list of ingredients in SPIRIVA HANDIHALER.

Symptoms of a serious allergic reaction to SPIRIVA HANDIHALER may include:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

What should I tell my doctor before using SPIRIVA HANDIHALER?

Before taking SPIRIVA HANDIHALER, tell your doctor about all your medical conditions, including if you:

• have kidney problems.
• have glaucoma. SPIRIVA HANDIHALER may make your glaucoma worse.
• have an enlarged prostate, problems passing urine, or a blockage in your bladder. SPIRIVA HANDIHALER may make these problems worse.
• are pregnant or plan to become pregnant. It is not known if SPIRIVA HANDIHALER could harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not known if SPIRIVA HANDIHALER passes into breast milk. You and your doctor will decide if SPIRIVA HANDIHALER is right for you while you breast-feed.
• have a severe allergy to milk proteins. Ask your doctor if you are not sure.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way SPIRIVA HANDIHALER works. SPIRIVA HANDIHALER is an anticholinergic medicine. You should not take other anticholinergic medicines while using SPIRIVA HANDIHALER, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

How should I take SPIRIVA HANDIHALER?

• Use SPIRIVA HANDIHALER exactly as prescribed. Use SPIRIVA HANDIHALER one time every day.
• Read the "Instructions for Use" at the end of this leaflet before you use SPIRIVA HANDIHALER. Talk with your doctor if you do not understand the instructions.
• Do not swallow SPIRIVA capsules.
• Only use SPIRIVA capsules with the HANDIHALER device.
• Do not use the HANDIHALER device to take any other medicine.
• SPIRIVA HANDIHALER comes as a powder in a SPIRIVA capsule that fits the HANDIHALER device. Each SPIRIVA capsule, containing only a small amount of SPIRIVA powder, is one full dose of medicine.
• Separate one blister from the blister card. Then take out one of the SPIRIVA capsules from the blister package right before you use it.
• After the capsule is pierced, take a complete dose of SPIRIVA HANDIHALER by breathing in the powder by mouth two times, using the HANDIHALER device (take 2 inhalations from one SPIRIVA capsule). See the " Instructions for Use " at the end of this leaflet.
• Throw away any SPIRIVA capsule that is not used right away after it is taken out of the blister package. Do not leave the SPIRIVA capsules open to air; they may not work as well.
• If you miss a dose, take it as soon as you remember. Do not use SPIRIVA HANDIHALER more than one time every 24 hours.
• If you use more than your prescribed dose of SPIRIVA HANDIHALER, call your doctor or a poison control center.

What should I avoid while using SPIRIVA HANDIHALER?

• Do not let the powder from the SPIRIVA capsule get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.
• SPIRIVA HANDIHALER can cause dizziness and blurred vision. Should you experience these symptoms you should use caution when engaging in activities such as driving a car or operating appliances or other machines.

What are the possible side effects of SPIRIVA HANDIHALER?

SPIRIVA HANDIHALER can cause serious side effects, including: Allergic reaction. Symptoms may include:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

• Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.

If you have these symptoms of bronchospasm, stop taking SPIRIVA HANDIHALER and call your doctor right away or go to the nearest hospital emergency room.

• New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:
  • eye pain
  • blurred vision
  • seeing halos (visual halos) or colored images along with red eyes

Using only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking SPIRIVA HANDIHALER and call your doctor right away.

• New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination.

If you have these symptoms of urinary retention, stop taking SPIRIVA HANDIHALER and call your doctor right away.

Other side effects with SPIRIVA HANDIHALER include:

• upper respiratory tract infection
• dry mouth
• sinus infection
• sore throat
• non-specific chest pain
• urinary tract infection
• indigestion
• runny nose
• constipation
• increased heart rate
• blurred vision

These are not all the possible side effects with SPIRIVA HANDIHALER. Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store SPIRIVA HANDIHALER?

• Do not store SPIRIVA capsules in the HANDIHALER device.
• Store SPIRIVA capsules in the sealed blister package at room temperature 68°F to 77°F (20°C to 25°C).
• Keep SPIRIVA capsules away from heat and cold (do not freeze).
• Store SPIRIVA capsules in a dry place. Throw away any unused SPIRIVA capsules that have been open to air.

Ask your doctor or pharmacist if you have any questions about storing your SPIRIVA capsules.

Keep SPIRIVA HANDIHALER, SPIRIVA capsules, and all medicines out of the reach of children.

General information about SPIRIVA HANDIHALER

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use SPIRIVA HANDIHALER for a purpose for which it has not been prescribed. Do not give SPIRIVA HANDIHALER to other people even if they have the same symptoms that you have. It may harm them.

For more information about SPIRIVA HANDIHALER, talk with your doctor. You can ask your doctor or pharmacist for information about SPIRIVA HANDIHALER that is written for health professionals.

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.

What are the ingredients in SPIRIVA HANDIHALER?

Active ingredient: tiotropium

Inactive ingredient: lactose monohydrate

What is COPD (Chronic Obstructive Pulmonary Disease)?

COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to breathe.

This Patient Information 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

As a predominantly renally excreted drug, 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 Clinical Pharmacology (12.3)].

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)].

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)].

SPIRIVA® (speh REE vah) HANDIHALER®

(tiotropium bromide inhalation powder)

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.

Taking your full daily dose of medicine requires 4 main steps.

Step 1. Opening your HANDIHALER device:

Step 2. Inserting the SPIRIVA capsule into your HANDIHALER device:

Step 3. Piercing the SPIRIVA capsule:

Step 4. Taking your full daily dose (2 inhalations from the same SPIRIVA capsule):

Caring for and storing your SPIRIVA HANDIHALER:

If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine:

Cleaning your HANDIHALER device:

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

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.

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.

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

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.

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.

• 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)

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)].

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.

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.

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.

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects (2, 8.6)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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.

Product: 50090-4248

NDC: 50090-4248-0 10 CAPSULE in a BLISTER PACK / 3 in a CARTON

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.

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.

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.

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).