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How To Use Your HandiHaler It's important to remember to take SPIRIVA every day and use your SPIRIVA HandiHaler correctly as prescribed by your doctor. This quick overview may help. For complete information on using the SPIRIVA HandiHaler, please see the Instructions for Use attached to your SPIRIVA HandiHaler prescription.
Familiarize yourself with the parts of your HandiHaler device: Important information about using your SPIRIVA HandiHaler:
• Do not swallow SPIRIVA capsules
1. Dust cap (lid)
• 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 3. Mouthpiece ridge
4. Base
IMPORTANT SAFETY INFORMATION
Do not use Spiriva® HandiHaler® (tiotropium bromide inhalation powder) if you are allergic to
5. Green piercing button
tiotropium or ipratropium (e.g., Atrovent®) or any of the ingredients in SPIRIVA. If your breathing 6. Center chamber
suddenly worsens, your face, throat, lips, or tongue swells, you get hives, itching or rash, stop taking SPIRIVA and seek immediate medical help.
7. Air intake vents
SPIRIVA HandiHaler is not a rescue medicine and should not be used for treating sudden breathing problems.
Do not swallow SPIRIVA capsules. The contents of the capsule should only be inhaled through your Taking your dose of SPIRIVA requires 4 main steps: mouth using the HandiHaler device.
If you have vision changes or eye pain or if you have difficulty passing urine or painful urination, stop taking SPIRIVA and call your doctor right away.
Tell your doctor if you have glaucoma, problems passing urine or an enlarged prostate, as these may worsen with SPIRIVA. Tell your doctor if you have kidney problems or are allergic to milk proteins. Ask your doctor if you are not sure. Also discuss with your doctor all the medicines you take, including eye drops.
The most common side effect with SPIRIVA is dry mouth. Others include constipation and trouble passing urine. For a complete list of reported side effects, ask your doctor or pharmacist.
Read the Patient Information and the step-by-step Instructions for Use for SPIRIVA before you 1. Open the HandiHaler device. Separate only one of the blisters
use your inhaler. from the blister card; then open the blister.
2. Insert the SPIRIVA capsule and close the mouthpiece firmly
Spiriva® HandiHaler® (tiotropium bromide inhalation powder) is a prescription medicine used once each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary against the gray base until you hear a click.
disease (COPD) by relaxing your airways and keeping them open. COPD includes chronic bronchitis, emphysema, or both.
3. Press the green piercing button once until it is flat (flush)
SPIRIVA HandiHaler also reduces the likelihood of flare-ups and worsening of COPD symptoms against the base, then release.
(COPD exacerbations).
You are encouraged to report negative side effects of prescription drugs to the FDA. 4. Breathe out completely. Then, with the HandiHaler in your
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
mouth, breathe in deeply until your lungs are full. You should Please see accompanying full Prescribing Information, including Patient Information and
hear or feel the SPIRIVA capsule vibrate (rattle). Instructions for Use.
Remember, to take your full daily dose, you must inhale twice Copyright 2014, Boehringer Ingelheim Pharmaceuticals, Inc. from the same SPIRIVA capsule.
All rights reserved. SV587504CONS 01/14 HIGHLIGHTS OF PRESCRIBING INFORMATION
WARNINGS AND PRECAUTIONS
These highlights do not include all the information needed to use SPIRIVA HandiHaler
• Not for acute use: Not for use as a rescue medication (5.1) safely and effectively. See full prescribing information for SPIRIVA HandiHaler.
• Immediate hypersensitivity reactions: Discontinue SPIRIVA HandiHaler at once and consider SPIRIVA® HandiHaler®
alternatives if immediate hypersensitivity reactions, including angioedema, bronchospasm, or (tiotropium bromide inhalation powder)
anaphylaxis, occur. Use with caution in patients with severe hypersensitivity to milk proteins. (5.2) Capsules for Respiratory Inhalation
• Paradoxical bronchospasm: Discontinue SPIRIVA HandiHaler and consider other treatments if DO NOT Swallow SPIRIVA Capsules
paradoxical bronchospasm occurs (5.3) FOR ORAL INHALATION ONLY with the HandiHaler Device
• 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) Initial U.S. Approval: 2004
• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyper- INDICATIONS AND USAGE
plasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (5.5) 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) • The most common adverse reactions (>5% incidence in the 1-year placebo-controlled trials) DOSAGE AND ADMINISTRATION
were upper respiratory tract infection, dry mouth, sinusitis, pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, and rhinitis (6.1) DO NOT swallow SPIRIVA capsules (2)For Use with the HandiHaler Device ONLY (2) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim
For Oral Inhalation ONLY (2) Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088
• Two inhalations of the powder contents of a single SPIRIVA capsule (18 mcg) once daily (2) DOSAGE FORMS AND STRENGTHS
Anticholinergics: May interact additively with concomitantly used anticholinergic medications. SPIRIVA capsules for oral inhalation: 18 mcg tiotropium powder, for use with HandiHaler device (3) Avoid administration of SPIRIVA HandiHaler with other anticholinergic-containing drugs. (7.2) USE IN SPECIFIC POPULATIONS
• Hypersensitivity to tiotropium, ipratropium or any components of SPIRIVA capsules (4) 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.
FULL PRESCRIBING INFORMATION: CONTENTS*
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
Hepatic Impairment DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Not for Acute Use 12.1 Mechanism of Action Immediate Hypersensitivity Reactions 12.2 Pharmacodynamics Paradoxical Bronchospasm 12.3 Pharmacokinetics Worsening of Narrow-Angle Glaucoma Worsening of Urinary Retention 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and Pharmacology Clinical Trials Experience HOW SUPPLIED/STORAGE AND HANDLING
Postmarketing Experience PATIENT COUNSELING INFORMATION
17.1 Instructions for Administering SPIRIVA HandiHaler Sympathomimetics, Methylxanthines, Steroids 17.2 Paradoxical Bronchospasm 7.2 Anticholinergics 17.3 Urinary Retention Cimetidine, Ranitidine 17.4 Visual Effects USE IN SPECIFIC POPULATIONS
17.5 Acute Exacerbation *Sections or subsections omitted from the full prescribing information are not listed. Labor and Delivery FULL PRESCRIBING INFORMATION
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 INDICATIONS AND USAGE
in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].
SPIRIVA HandiHaler (tiotropium bromide inhalation powder) is indicated for the long-term, once- DOSAGE FORMS AND STRENGTHS
daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA HandiHaler is indicated SPIRIVA HandiHaler consists of SPIRIVA capsules and a HandiHaler device. SPIRIVA capsules to reduce exacerbations in COPD patients.
contain 18 mcg dry powder formulation 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. DOSAGE AND ADMINISTRATION
DO NOT SWALLOW SPIRIVA CAPSULES
SPIRIVA HandiHaler is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of SPIRIVA capsules [see WARNINGS AND PRECAUTIONS (5.2)]. FOR USE WITH HANDIHALER DEVICE ONLY
In clinical trials and postmarketing experience with SPIRIVA HandiHaler, immediate hypersensi- FOR ORAL INHALATION ONLY
tivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.
SPIRIVA capsules must not be swallowed as the intended effects on the lungs will not be
obtained. The contents of the SPIRIVA capsules are only for oral inhalation and should
WARNINGS AND PRECAUTIONS
only be used with the HandiHaler device [see Overdosage (10)].
5.1 Not for Acute Use
The recommended dose of SPIRIVA HandiHaler is two inhalations of the powder contents of one SPIRIVA HandiHaler is intended as a once-daily maintenance treatment for COPD and is not SPIRIVA capsule, once-daily, with the HandiHaler device [see Patient Counseling Information (17)].
indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).
For administration of SPIRIVA HandiHaler, a SPIRIVA capsule is placed into the center chamber of 5.2 Immediate Hypersensitivity Reactions
the HandiHaler device. The SPIRIVA capsule is pierced by pressing and releasing the green piercing Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administra- stream when the patient inhales through the mouthpiece [see Patient Counseling Information (17)].
tion of SPIRIVA HandiHaler. If such a reaction occurs, therapy with SPIRIVA HandiHaler should be No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired 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® Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA HandiHaler® (tiotropium bromide inhalation powder). In addition, SPIRIVA HandiHaler should be HandiHaler treatment group, but were <1% in excess of the placebo group.
used with caution in patients with severe hypersensitivity to milk proteins.
Other reactions that occurred in the SPIRIVA HandiHaler group at a frequency of 1% to 3% in 5.3 Paradoxical Bronchospasm
the placebo-controlled trials where the rates exceeded that in the placebo group include: Body Inhaled medicines, including SPIRIVA HandiHaler, can produce paradoxical bronchospasm. If this as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, occurs, treatment with SPIRIVA HandiHaler should be stopped and other treatments considered.
paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise 5.4 Worsening of Narrow-Angle Glaucoma
specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma. and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glau- Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); coma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed physician immediately should any of these signs or symptoms develop.
in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycar- dia, angioedema, and urinary retention.
5.5 Worsening of Urinary Retention
In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection SPIRIVA HandiHaler should be used with caution in patients with urinary retention. Prescribers increased with age [see Use in Specific Populations (8.5)].
and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a Two multicenter, 6-month, controlled studies evaluated SPIRIVA HandiHaler in patients with physician immediately should any of these signs or symptoms develop.
COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.
5.6 Renal Impairment
As a predominantly renally excreted drug, patients with moderate to severe renal impairment
4-Year Trial (creatinine clearance of ≤50 mL/min) treated with SPIRIVA HandiHaler should be monitored The data described below reflect exposure to SPIRIVA HandiHaler in 5992 COPD patients in a closely for anticholinergic side effects [see Clinical Pharmacology (12.3)].
4-year placebo-controlled trial. In this trial, 2986 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator The following adverse reactions are described, or described in greater detail, in other sections: FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic • Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)] hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse • Paradoxical bronchospasm [see Warnings and Precautions (5.3)] reactions were analyzed with a frequency of ≥3% in the SPIRIVA HandiHaler group where the • Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)] rates in the SPIRIVA HandiHaler group exceeded placebo by ≥1%, adverse reactions included • Worsening of urinary retention [see Warnings and Precautions (5.5)] (SPIRIVA HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), 6.1 Clinical Trials Experience
insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates Additional Adverse Reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with SPIRIVA HandiHaler than placebo include: dehydration, skin ulcer, 6-Month to 1-Year Trials stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.
The data described below reflect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA 6.2 Postmarketing Experience
HandiHaler was studied in two 1-year placebo-controlled trials, two 1-year active-controlled Adverse reactions have been identified during worldwide post-approval use of SPIRIVA HandiHaler. trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 Because these reactions are reported voluntarily from a population of uncertain size, it is not patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a always possible to reliably estimate their frequency or establish a causal relationship to drug day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% exposure. These adverse reactions are: application site irritation (glossitis, mouth ulceration, Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycar- symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these dia, throat irritation, and urticaria.
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 7.1 Sympathomimetics, Methylxanthines, Steroids
mild and often resolved during continued treatment. Other reactions reported in individual SPIRIVA HandiHaler has been used concomitantly with short-acting and long-acting sympatho- patients and consistent with possible anticholinergic effects included constipation, tachycardia, mimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention.
increases in adverse drug reactions.
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 There is potential for an additive interaction with concomitantly used anticholinergic frequency of ≥3% in the SPIRIVA HandiHaler group in the 1-year placebo-controlled trials where medications. Therefore, avoid coadministration of SPIRIVA HandiHaler with other anticholin- the rates in the SPIRIVA HandiHaler group exceeded placebo by ≥1%. The frequency of ergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see corresponding reactions in the ipratropium-controlled trials is included for comparison. Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].
Table 1 Adverse Reactions (% Patients) in One-Year COPD Clinical Trials
7.3 Cimetidine, Ranitidine
Body System (Event)
Placebo-Controlled Trials Ipratropium-
No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Body as a Whole
Teratogenic Effects, Pregnancy Category C. Chest Pain (non-specific) There are no adequate and well-controlled studies in pregnant women. SPIRIVA HandiHaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Gastrointestinal System Disorders
No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis in rats and rabbits, respectively. These dose multiples may be over-estimated due to difficulties in Resistance Mechanism Disorders
measuring deposited doses in animal inhalation studies.
8.2 Labor and Delivery
The safety and effectiveness of SPIRIVA HandiHaler has not been studied during labor and delivery.
Respiratory System (Upper)
8.3 Nursing Mothers
Upper Respiratory Tract Infection 41 Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if SPIRIVA HandiHaler is administered to a nursing 8.4 Pediatric Use
Skin and Appendage Disorders
SPIRIVA HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of SPIRIVA HandiHaler in pediatric patients have Urinary Tract Infection not been established.
8.5 Geriatric Use
as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was Of the total number of patients who received Spiriva® HandiHaler® (tiotropium bromide dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of inhalation powder) in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, tiotropium is predominantly a site-specific effect.
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 (differ- ences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD, the higher frequency of constipation and urinary tract infections with increasing age was observed number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was in the SPIRIVA HandiHaler group in the placebo-controlled studies. The differences from placebo higher in the SPIRIVA HandiHaler group as compared with placebo. This difference was appar- for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from ent using both the Bazett (QTcB) [20 (20%) patients vs 12 (12%) patients] and Fredericia (QTcF) placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in [16 (16%) patients vs 1 (1%) patient] corrections of QT for heart rate. No patients in either effectiveness were observed among these groups. Based on available data, no adjustment of group had either QTcB or QTcF of >500 msec. Other clinical studies with SPIRIVA HandiHaler SPIRIVA HandiHaler dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
did not detect an effect of the drug on QTc intervals. 8.6 Renal Impairment
The effect of SPIRIVA HandiHaler on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received SPIRIVA Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated HandiHaler 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG with SPIRIVA HandiHaler should be monitored closely for anticholinergic side effects [see Dosage assessments were performed at baseline and throughout the dosing interval following the first and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].
and last dose of study medication. Relative to placebo, the maximum mean change from base- 8.7 Hepatic Impairment
line in study-specific QTc interval was 3.2 msec and 0.8 msec for SPIRIVA HandiHaler 18 mcg The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.
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 is administered by dry powder inhalation. In common with other inhaled drugs, the tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium.
the lung, the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Accidental Ingestion
Acute intoxication by inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is Absorption
not well-absorbed systemically.
Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of A case of overdose has been reported from postmarketing experience. A female patient was 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental the chemical structure of the compound (quaternary ammonium compound) that tiotropium is status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, SPIRIVA poorly absorbed from the gastrointestinal tract. The effect of food on tiotropium's bioavailability HandiHaler was discontinued, and the constipation was treated with an enema. The patient has not been studied. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. recovered and was discharged on the same day.
Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation.
No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and Tiotropium shows a volume of distribution of 32 L/kg indicating that the drug binds extensively 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. to tissues. The human plasma protein binding for tiotropium is 72%. At steady state, peak These dose multiples may be over-estimated due to difficulties in measuring deposited doses in tiotropium plasma levels in COPD patients were 17 to 19 pg/mL when measured 5 minutes animal inhalation studies.
after dry powder inhalation of an 18 mcg dose and decreased in a multi-compartmental manner. Steady-state trough plasma concentrations were 3 to 4 pg/mL. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concen- SPIRIVA HandiHaler consists of a capsule dosage form containing a dry powder formulation of trations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the tiotropium intended for oral inhalation only with the HandiHaler device.
Each light green, hard gelatin SPIRIVA capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier.
The extent of metabolism appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an The dry powder formulation within the SPIRIVA capsule is intended for oral inhalation only.
ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, The active component of SPIRIVA HandiHaler is tiotropium. The drug substance, tiotropium neither of which binds to muscarinic receptors.
bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is In vitro experiments with human liver microsomes and human hepatocytes suggest that a chemically described as (1α, 2β, 4β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl- fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the 3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate. It is a synthetic, non-chiral, urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic is sparingly soluble in water and soluble in methanol.
pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, The structural formula is: and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
EliminationThe terminal elimination half-life of tiotropium was between 5 and 6 days following inhalation. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating active secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter.
Drug Interactions Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and C19H22NO4S2Br • H2O.
cimetidine 400 mg three times daily or ranitidine 300 mg once daily was conducted. Concomitant The HandiHaler device is an inhalation device used to inhale the dry powder contained in the administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% SPIRIVA capsule. The dry powder is delivered from the HandiHaler device at flow rates as low decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 the pharmacokinetics of tiotropium.
adult patients with COPD and severely compromised lung function [mean FEV 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) Geriatric Patients through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug As expected for drugs predominantly excreted renally, advanced age was associated with a delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min inspiratory flow through the HandiHaler device, which may vary from patient to patient, and in COPD patients >70 years), which may be explained by decreased renal function. Tiotropium may vary with the exposure time of the SPIRIVA capsule outside the blister pack.
excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma concentrations were numerically increased with advancing age within 12.1 Mechanism of Action
COPD patients (43% increase in AUC0-4 after dry powder inhalation), which was not significant Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholin- when considered in relation to inter- and intra-individual variability [see Dosage and ergic. It has similar affinity to the subtypes of muscarinic receptors, M Administration (2) and Use in Specific Populations (8.5)].
1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M 3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown Since tiotropium is predominantly renally excreted, renal impairment was associated with with human and animal origin receptors and isolated organ preparations. In preclinical in vitro increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder inhalation. Mild renal impairment (creatinine clearance of 50 to Mean FEV1 Over Time (prior to and after administration of study drug) on
80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*
(39% increase in AUC 0-4 after intravenous infusion). In COPD patients with moderate to severe renal impairment (creatinine clearance of <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC0-4), which was confirmed by plasma concentrations after dry powder inhalation. Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Spiriva® HandiHaler® (tiotropium bromide inhalation powder) should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Use in Specific Populations (8.6)].
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
13
*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
SPIRIVA HandiHaler and placebo groups, respectively, completed the trial. The data for the remaining patients No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at were imputed using the last observation or least favorable observation carried forward.
tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study in female mice at Results of each of the 1-year ipratropium-controlled trials were similar to the results of the doses up to 0.145 mg/kg/day, and in a 101-week inhalation study in male mice at doses up to 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2.
0.002 mg/kg/day. These doses correspond to approximately 25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. These dose Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92,
multiples may be over-estimated due to difficulties in measuring deposited doses in animal Respectively for One of the Two Ipratropium-Controlled Studies*
inhalation studies.
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 0.078 mg/kg/day or greater (approximately 35 times the RHDID on a mg/m2 basis). No such effects were observed at 0.009 mg/kg/day (approximately 4 times than the RHDID on a mg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times the RHDID on a mg/m2 basis). These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 13.2 Animal Toxicology and Pharmacology
69 patients in the SPIRIVA HandiHaler and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable Reproductive Toxicology Studies observation carried forward.
No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively. These doses correspond A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that to approximately 660 and 6 times the RHDID on a mg/m2 basis, respectively. However, in rats, bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup regardless of whether SPIRIVA HandiHaler was administered in the morning or in the evening.
weights, and a delay in pup sexual maturation were observed at inhalation tiotropium doses of Throughout each week of the one-year treatment period in the two placebo-controlled trials, ≥0.078 mg/kg (approximately 35 times the RHDID on a mg/m2 basis). In rabbits, an increase patients taking SPIRIVA HandiHaler had a reduced requirement for the use of rescue short- in post-implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approximately acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared 360 times the RHDID on a mg/m2 basis). Such effects were not observed at inhalation doses of to placebo, was demonstrated in one of the two 6-month studies.
0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively. These doses correspond to 4-Year Effects on Lung Function approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of SPIRIVA HandiHaler on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and The SPIRIVA HandiHaler clinical development program consisted of six Phase 3 studies in 2663 theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, patients with COPD (1308 receiving SPIRIVA HandiHaler): two 1-year, placebo control ed studies, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post- had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3). second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less SPIRIVA HandiHaler maintained improvements in trough (pre-dose) FEV1 (adjusted means over than or equal to 0.7.
time: 87 to 103 mL) throughout the 4 years of the study (Figure 3).
In these studies, SPIRIVA HandiHaler, administered once-daily in the morning, provided Figure 3 Trough (pre-dose) FEV1 Mean Values at Each Time Point
improvement in lung function (FEV1), with peak effect occurring within 3 hours following the Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo- Tiotropium (n = 2494) Control (n = 2363) 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.
6-Month to 1-Year Effects on Lung Function In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV 1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance.
Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measure- In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed ments. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial function tests after Day 30 and non-missing baseline value were included in the analysis. FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with SPIRIVA HandiHaler, which persisted over the The effect of SPIRIVA HandiHaler on COPD exacerbations was evaluated in two clinical trials: spirometric observational period. Effectiveness was maintained for 24 hours after a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a administration over the 6-month treatment period.
Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Spiriva® HandiHaler® Copyright  2014 Boehringer Ingelheim International GmbH (tiotropium bromide inhalation powder) significantly reduced the proportion of COPD patients who ALL RIGHTS RESERVED experienced exacerbations compared to placebo (27.9% vs 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with IT1600AED292014 10004551/12 IT5300H 75740-08 hospitalization due to COPD exacerbations in patients who used SPIRIVA HandiHaler compared to placebo was 7.0% vs 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056.
Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. SPIRIVA HandiHaler significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; SPIRIVA® (speh REE vah) HandiHaler®
p<0.002) compared to placebo. The median time to first exacerbation was delayed from (tiotropium bromide inhalation powder)
12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the SPIRIVA HandiHaler group.
16
HOW SUPPLIED/STORAGE AND HANDLING
SPIRIVA HandiHaler consists of SPIRIVA capsules and the HandiHaler device. SPIRIVA capsules Do NOT swallow 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 Important Information: Do not swallow SPIRIVA capsules. 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 capsules should only be used with the HandiHaler device and inhaled
that the HandiHaler device is only to be used with SPIRIVA capsules.
through your mouth (oral inhalation).
SPIRIVA capsules are packaged in an aluminum/aluminum blister card and joined along a Read the information that comes with your SPIRIVA HandiHaler before you perforated-cut line. SPIRIVA capsules should always be stored in the blister and only removed start using it and each time you refill your prescription. There may be new immediately before use. The drug should be used immediately after the packaging over an individual SPIRIVA capsule is opened.
information. This leaflet does not take the place of talking with your doctor about The following packages are available: your medical condition or your treatment.
• carton containing 5 SPIRIVA capsules (1 unit-dose blister card) and 1 HandiHaler What is SPIRIVA HandiHaler?
inhalation device (NDC 0597-0075-75) (institutional pack) • carton containing 30 SPIRIVA capsules (3 unit-dose blister cards) and 1 HandiHaler • SPIRIVA HandiHaler is a prescription medicine used each day (a maintenance inhalation device (NDC 0597-0075-41) medicine) to control symptoms of chronic obstructive pulmonary disease • carton containing 90 SPIRIVA capsules (9 unit-dose blister cards) and 1 HandiHaler (COPD), including chronic bronchitis and emphysema.
inhalation device (NDC 0597-0075-47) • 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 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled
feel like it is easier to breathe on the first day, but it may take longer for you to Room Temperature].
feel the full effects of the medicine. SPIRIVA HandiHaler works best and may The SPIRIVA capsules should not be exposed to extreme temperature or moisture. Do not store help make it easier to breathe when you use it every day. SPIRIVA capsules in the HandiHaler device.
• SPIRIVA HandiHaler reduces the likelihood of flare-ups and worsening of PATIENT COUNSELING INFORMATION
COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as See FDA-approved Patient Labeling an increase or new onset of more than one COPD symptom such as cough, 17.1 Instructions for Administering SPIRIVA HandiHaler
mucus, shortness of breath, and wheezing that requires medicine beyond It is important for patients to understand how to correctly administer SPIRIVA capsules using your rescue medicine.
the HandiHaler device [see Patient Counseling Information (17)]. Instruct patients that SPIRIVA SPIRIVA HandiHaler is not a rescue medicine and should not be used
capsules should only be administered via the HandiHaler device and the HandiHaler device should not be used for administering other medications. Remind patients that the contents of for treating sudden breathing problems. Your doctor may give you other
SPIRIVA capsules are for oral inhalation only and must not be swallowed.
medicine to use for sudden breathing problems.
Instruct patients always to store SPIRIVA capsules in sealed blisters and to remove only one It is not known if SPIRIVA HandiHaler is safe and effective in children.
SPIRIVA capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional SPIRIVA capsules that are exposed to air (i.e., not intended for Who should not take SPIRIVA HandiHaler?
immediate use).
17.2 Paradoxical Bronchospasm
Do not use SPIRIVA HandiHaler if you:
Inform patients that SPIRIVA HandiHaler can produce paradoxical bronchospasm. Advise patients • are allergic to tiotropium, ipratropium (Atrovent®), or any of the ingredients that if paradoxical bronchospasm occurs, patients should discontinue SPIRIVA HandiHaler.
in SPIRIVA HandiHaler. See the end of this leaflet for a complete list of 17.3 Urinary Retention
ingredients in SPIRIVA HandiHaler. Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic Symptoms of a serious allergic reaction to SPIRIVA HandiHaler may include: hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician o raised red patches on your skin (hives) immediately should any of these signs or symptoms develop. 17.4 Visual Effects
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle o swelling of the face, lips, tongue, and throat that may cause difficulty in glaucoma. Inform patients to consult a physician immediately should any of these signs and breathing or swallowing symptoms develop. Advise patients that miotic eye drops alone are not considered to be If you have these symptoms of an allergic reaction, stop taking SPIRIVA HandiHaler effective treatment. and call your doctor right away or go to the nearest hospital emergency room.
Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.
What should I tell my doctor before using SPIRIVA HandiHaler?
Since dizziness and blurred vision may occur with the use of SPIRIVA HandiHaler, caution patients Before taking SPIRIVA HandiHaler, tell your doctor about all your medical
about engaging in activities such as driving a vehicle or operating appliances or machinery.
conditions, including if you:
17.5 Acute Exacerbation
• have kidney problems.
Instruct patients that SPIRIVA HandiHaler is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).
• 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.
Boehringer Ingelheim Pharmaceuticals, Inc.
• are pregnant or plan to become pregnant. It is not known if SPIRIVA HandiHaler Ridgefield, CT 06877 USA could harm your unborn baby. • are breast-feeding or plan to breast-feed. It is not known if SPIRIVA Boehringer Ingelheim International GmbH HandiHaler passes into breast milk. You and your doctor will decide if SPIRIVA HandiHaler is right for you while you breast-feed.
Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.
• have a severe allergy to milk proteins. Ask your doctor if you are not sure.
SPIRIVA® and HandiHaler® are registered trademarks and are used under license from Tell your doctor about all the medicines you take, including prescription
Boehringer Ingelheim International GmbH.
and non-prescription medicines and eye drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way These are not all the possible side effects with SPIRIVA HandiHaler. Tell your Spiriva® HandiHaler® (tiotropium bromide inhalation powder) works. SPIRIVA doctor if you have any side effect that bothers you or that does not go away.
HandiHaler is an anticholinergic medicine. You should not take other anticholinergic Call your doctor for medical advice about side effects. You may report side medicines while using SPIRIVA HandiHaler, including ipratropium. Ask your doctor effects to FDA at 1-800-FDA-1088. 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 How do I store SPIRIVA HandiHaler?
your doctor and pharmacist when you get a new medicine. • Do not store SPIRIVA capsules in the HandiHaler device.
How should I take SPIRIVA HandiHaler?
• Store SPIRIVA capsules in the sealed blister package at room temperature between 68oF to 77oF (20o to 25oC). • Use SPIRIVA HandiHaler exactly as prescribed. Use SPIRIVA HandiHaler one • Keep SPIRIVA capsules away from heat and cold (do not freeze). • Store SPIRIVA capsules in a dry place. Throw away any unused SPIRIVA • Read the "Instructions for Use" at the end of this leaflet before you use capsules that have been open to air.
SPIRIVA HandiHaler. Talk with your doctor if you do not understand Ask your doctor or pharmacist if you have any questions about storing your the instructions. SPIRIVA capsules. • Do not swallow SPIRIVA capsules.
Keep SPIRIVA HandiHaler, SPIRIVA capsules, and all medicines out of the
• Only use SPIRIVA capsules with the HandiHaler device.
reach of children.
• Do not use the HandiHaler device to take any other medicine.
• SPIRIVA HandiHaler comes as a powder in a SPIRIVA capsule that fits the General information about SPIRIVA HandiHaler
HandiHaler device. Each SPIRIVA capsule, containing only a small amount of Medicines are sometimes prescribed for purposes other than those listed in SPIRIVA powder, is one full dose of medicine. Patient Information leaflets. Do not use SPIRIVA HandiHaler for a purpose for • Separate one blister from the blister card. Then take out one of the SPIRIVA which it has not been prescribed. Do not give SPIRIVA HandiHaler to other people capsules from the blister package right before you use it. even if they have the same symptoms that you have. It may harm them.
• 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 For more information about SPIRIVA HandiHaler, talk with your doctor. You can (take 2 inhalations from one SPIRIVA capsule). See the "Instructions for
ask your doctor or pharmacist for information about SPIRIVA HandiHaler that is Use" at the end of this leaflet.
written for health professionals.
• Throw away any SPIRIVA capsule that is not used right away after it is taken For more information about SPIRIVA HandiHaler, go to www.SPIRIVA.com or out of the blister package. Do not leave the SPIRIVA capsules open to air; they scan the code below, or call Boehringer Ingelheim Pharmaceuticals, Inc. at may not work as well. 1-800-542-6257 or (TTY) 1-800-459-9906.
• 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 What are the ingredients in SPIRIVA HandiHaler?
vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.
Active ingredient: tiotropium • SPIRIVA HandiHaler can cause dizziness and blurred vision. Should you Inactive ingredient: lactose monohydrate experience these symptoms you should use caution when engaging in What is COPD (Chronic Obstructive Pulmonary Disease)?
activities such as driving a car or operating appliances or other machines.
What are the possible side effects of SPIRIVA HandiHaler?
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 SPIRIVA HandiHaler can cause serious side effects, including: Allergic become narrow. So, air moves out of your lungs more slowly. This makes it hard
reaction. Symptoms may include:
o raised red patches on your skin (hives) This Patient Information has been approved by the U.S. Food and Drug o 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 Boehringer Ingelheim Pharmaceuticals, Inc. and call your doctor right away or go to the nearest hospital emergency room.
Ridgefield, CT 06877 USA • Sudden narrowing and blockage of the airways into the lungs
(bronchospasm). Your breathing suddenly gets worse.
Boehringer Ingelheim International GmbH If you have these symptoms of bronchospasm, stop taking SPIRIVA HandiHaler SPIRIVA® and HandiHaler® are registered trademarks and are used under license from and call your doctor right away or go to the nearest hospital emergency room.
Boehringer Ingelheim International GmbH.
• New or worsened increased pressure in the eyes (acute narrow-
Copyright  2014 Boehringer Ingelheim International GmbH angle glaucoma). Symptoms of acute narrow-angle glaucoma may include:
ALL RIGHTS RESERVED Revised: April 2014 o blurred vision o seeing halos (visual halos) or colored images along with red eyes IT1600AED292014 10004551/12 IT5300H 75740-08 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 • sinus infection • increased heart rate • non-specific chest pain • blurred vision • urinary tract infection Instructions for Use
• Open the mouthpiece by pulling the mouthpiece ridge SPIRIVA® (speh REE vah) HandiHaler®
up and away from the base so the center (tiotropium bromide inhalation powder)
chamber is showing. (See Figure F) Do not swallow SPIRIVA capsules.
Step 2. Inserting the SPIRIVA capsule into your HandiHaler device:
Important Information about using your SPIRIVA HandiHaler
Each day, separate only 1 of the blisters from the blister card by tearing along the perforated line. (See Figure G) • Do not swallow SPIRIVA capsules.
Use With HandiHaler
• SPIRIVA capsules should only be used with the HandiHaler device
Only e Use
and inhaled through your mouth (oral inhalation).
N (01) 1 03 0597-0075-4 N (01) 1 03 0597-0075 ral Inhal
For Or Imm
• Do not use your HandiHaler device to take any other medicine.
(01) 1 03 0597-0075-4 Op N (01) 1 03 0597-00 r O Immediat
ral Inhal
tio y Be -47
First read the Patient Information, then read these Instructions for Use before Op N (01) 1 03 0597-0075 you start to use SPIRIVA HandiHaler and each time you refill your prescription. There may be new information. Becoming familiar with your HandiHaler device
Remove the SPIRIVA capsule from the blister:
Exp. MMM YY Lot 00 N (01) 1 03 0597- th HandiHale
and SPIRIVA capsules:
• Do not cut the foil or use sharp instruments to take
out the SPIRIVA capsule from the blister. Your SPIRIVA HandiHaler comes with SPIRIVA capsules in blister packaging and a p. MMM YY Lot 000000X Exp. MMM YY Lot 000000X 01) 1 03 0597-0075-47 N (01) 1 03 0597-0075-47w
• Bend 1 of the blister corners with an arrow and HandiHaler device. Use the new HandiHaler device provided with your medicine.
Or Immediatel
al Inhalation Only
r Or Immediately
al Inhalation
separate the aluminum foil layers.
The parts of your HandiHaler device include:
• Peel back the printed foil until you see the whole SPIRIVA capsule. (See Figure H) 1. dust cap (lid) • If you have opened more than 1 blister to the air, the extra SPIRIVA capsule should not be used and 3. mouthpiece ridge should be thrown away.
5. green piercing button Place the SPIRIVA capsule in the center chamber of your 6. center chamber HandiHaler device. (See Figure I) 7. air intake vents Each SPIRIVA capsule is packaged in a blister. (See Figure B) Use With HandiHaler
Only e Use
N (01) 1 03 0597-0075-4 Op N (01) 1 03 0597-0075 O Immedia
ral Inhal
N (01) 1 03 0597-0075-4 h HandiHaler
Op N (01) 1 03 0597-0075 r O Immediat
ral Inhal
Close the mouthpiece firmly against the gray base Op N (01) 1 03 0597-0075 until you hear a click. Leave the dust cap (lid) open. • Each SPIRIVA capsule contains only a small amount of powder. (See Figure C) This is 1 full dose. • Do not open the SPIRIVA capsule or it may not
Step 3. Piercing the SPIRIVA capsule:
• Hold your HandiHaler device with the mouthpiece pointed up. (See Figure K) Taking your full daily dose of medicine requires 4 main steps.
• Press the green piercing button once until it is flat Step 1. Opening your HandiHaler device:
(flush) against the base, then release. This is how After removing your HandiHaler device from the pouch: you make holes in the SPIRIVA capsule so that you get your medicine when you breathe in.
• Open the dust cap (lid) by pressing the green piercing button. (See Figure D) • Do not press the green button more than one time.
• Do not shake your HandiHaler device.
• The piercing of the SPIRIVA capsule may produce
small gelatin pieces. Some of these small pieces may pass through the screen of your HandiHaler device into your mouth or throat when you breathe • Pull the dust cap (lid) upwards away from the in your medicine. This is normal. The small pieces base to expose the mouthpiece. (See Figure E) of gelatin should not harm you.
Step 4. Taking your full daily dose (2 inhalations from the same Spiriva®
• Open the base by lifting the green piercing HandiHaler® (tiotropium bromide inhalation powder) capsule):
button and check the center chamber for pieces of the SPIRIVA capsule. SPIRIVA capsule pieces in Breathe out completely in 1 breath, emptying your
the center chamber can cause a SPIRIVA capsule lungs of any air. (See Figure L) • Turn your HandiHaler device upside down and Important: Do not breathe into your HandiHaler device.
gently, but firmly, tap to remove the SPIRIVA capsule pieces. Call your doctor for instructions.
Cleaning your HandiHaler device:
Clean your HandiHaler device as needed. (See Figure R) With your next breath, take your medicine:
• It takes 24 hours to air dry your HandiHaler
• Hold your head in an upright position while
device after you clean it.
you are looking straight ahead. (See Figure M)
• Do not use cleaning agents or detergents.
• Raise your HandiHaler device to your mouth in a • Do not place your HandiHaler device in the
horizontal position. Do not block the air intake vents.
dishwasher for cleaning.
• Close your lips tightly around the mouthpiece. • Breathe in deeply until your lungs are full. You
• Open the dust cap and mouthpiece should hear or feel the SPIRIVA capsule vibrate
• Open the base by lifting the green piercing button.
(rattle). (See Figure M) • Look in the center chamber for SPIRIVA capsule pieces or powder buildup. If seen, tap out.
• Hold your breath for a few seconds and, at the same • Rinse your HandiHaler device with warm water, time, take your HandiHaler device out of your mouth. pressing the green piercing button a few times so • Breathe normally again. that the center chamber and the piercing needle The rattle tells you that you breathed in correctly. If you is under the running water. Check that any powder do not hear or feel a rattle, see the section, "If you do not buildup or SPIRIVA capsule pieces are removed.
hear or feel the SPIRIVA capsule rattle as you breathe in • Dry your HandiHaler device well by tipping the excess water out on a paper towel. Air-dry afterwards, leaving the dust cap, mouthpiece, To get your full daily dose, you must again, breathe
and base open by fully spreading it out so that it out completely (See Figure N) and for a second time,
dries completely.
breathe in (See Figure O) from the same SPIRIVA
• Do not use a hair dryer to dry your HandiHaler device.
• Do not use your HandiHaler device when it is wet.
If needed, you may clean the outside of the Important: Do not press the green piercing button
mouthpiece with a clean damp cloth. Helpful Hints to help ensure that you are properly taking your full daily
dose of SPIRIVA HandiHaler: Remember: To get your full medicine dose each day, you • Press the green piercing button 1 time; Breathe in 2 times; Breathe
must breathe in 2 times from the same SPIRIVA capsule. out completely before each of the 2 inhalations.
Make sure you breathe out completely each time before • Always use the new HandiHaler device provided with your medicine.
you breathe in from your HandiHaler device. • Keep your HandiHaler device with the mouthpiece pointed up when pressing the green piercing button.
• Press the green piercing button 1 time to pierce the SPIRIVA capsule.
• Do not breathe out into your HandiHaler device.
• Keep your HandiHaler device in a horizontal position and keep your head upright, looking straight ahead, when breathing in.
• Check the center chamber of your HandiHaler device for SPIRIVA capsule Caring for and storing your SPIRIVA HandiHaler:
pieces or powder build-up. If pieces or powder are seen, tap out before use.
• After taking your daily dose, open the mouthpiece • Clean your HandiHaler as needed and dry thoroughly.
and tip out the used SPIRIVA capsule into your trash can, without touching it.
For more information, ask your doctor or pharmacist, or go to www.spiriva.com, • Remove any SPIRIVA capsule pieces or SPIRIVA or scan the code below, or call 1-800-542-6257.
powder buildup by turning your HandiHaler device upside down and gently, but firmly, tapping it. (See Figure P) Then, close the mouthpiece and dustcap for storage. • Do not store your HandiHaler device and SPIRIVA
capsules (blisters) in a damp moist place. Always This Instructions for Use has been approved by the U.S. Food and Drug Administration.
store SPIRIVA capsules in the sealed blisters.
If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Do not press the green piercing button again.
Hold your HandiHaler device with the mouthpiece pointed Boehringer Ingelheim International GmbH up and tap your HandiHaler device gently on a table. (See SPIRIVA® and HandiHaler® are registered trademarks and are used under license from Boehringer Ingelheim International GmbH.
Check to see that the mouthpiece is completely closed. Copyright  2014 Boehringer Ingelheim International GmbH Breathe out completely before deeply breathing in again ALL RIGHTS RESERVED with the mouthpiece in your mouth. (See Figure O) Revised: April 2014 If you still do not hear or feel the SPIRIVA capsule rattle after repeating the above steps: IT1600AED292014 10004551/12 IT5300H 75740-08 • Throw away the SPIRIVA capsule.

Source: https://www.spiriva.com/pdf/copd/SPIRIVA_HandiHaler_Instructions.pdf