ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adversereactions are described, or described in greater detail, in other sections:Immediate hypersensitivityreactions [see Warnings and Precautions (5.2) ]Paradoxical bronchospasm [seeWarnings and Precautions (5.3) ]Worsening of narrow-angleglaucoma [see Warnings and Precautions (5.4) ]Worsening of urinary retention [seeWarnings and Precautions (5.5) ]. Immediate hypersensitivityreactions [see Warnings and Precautions (5.2) ]. Paradoxical bronchospasm [seeWarnings and Precautions (5.3) ]. Worsening of narrow-angleglaucoma [see Warnings and Precautions (5.4) ]. Worsening of urinary retention [seeWarnings and Precautions (5.5) ]. The most common adverse reactions (>5% incidence in the 1-yearplacebo-controlled trials) were upper respiratory tract infection, dry mouth, sinusitis,pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, andrhinitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact BoehringerIngelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDAat 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions (>5% incidence in the 1-yearplacebo-controlled trials) were upper respiratory tract infection, dry mouth, sinusitis,pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, andrhinitis (6.1) 6.1 Clinical Trials Experience. Because clinical trialsare conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed inpractice.6-Month to 1-Year TrialsThedata described below reflect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA HandiHaler was studied in two 1-year placebo-controlled trials, two1-year active-controlled trials, and two 6-month placebo-controlled trials inpatients with COPD. In these trials, 1308 patientswere treated with SPIRIVA HandiHaler at the recommended dose of 18 mcgonce day. The population had an age ranging from 39 to 87 years with 65% to85% males, 95% Caucasian, and had COPD with mean pre-bronchodilator forcedexpiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, orsymptomatic prostatic hypertrophy or bladder outlet obstruction were excludedfrom these trials. An additional 6-month trial conducted in VeteransAffairs setting is not included in this safety database because only seriousadverse events were collected.Themost commonly reported adverse drug reaction was dry mouth. Dry mouth wasusually mild and often resolved during continued treatment. Other reactionsreported in individual patients and consistent with possible anticholinergiceffects included constipation, tachycardia, blurred vision, glaucoma (new onsetor worsening), dysuria, and urinary retention.Fourmulticenter, 1-year, placebo-controlled and active-controlled trials evaluatedSPIRIVA HandiHaler in patients with COPD. Table shows all adverse reactionsthat occurred with frequency of >=3% in the SPIRIVA HandiHalergroup in the 1-year placebo-controlled trials where the rates in the SPIRIVA HandiHalergroup exceeded placebo by >=1%. The frequency of corresponding reactions in theipratropium-controlled trials is included for comparison.Table Adverse Reactions(% Patients) in One-Year COPD Clinical TrialsBody System (Event)Placebo-Controlled TrialsIpratropium-Controlled Trials SPIRIVA(n 550)Placebo(n 371)SPIRIVA(n 356)Ipratropium(n 179)Body as WholeChest Pain (non-specific)7552Edema, Dependent5435Gastrointestinal System DisordersDry Mouth163126Dyspepsia6511Abdominal Pain5366Constipation4211Vomiting4212Musculoskeletal SystemMyalgia4343Resistance Mechanism DisordersInfection4313Moniliasis4232Respiratory System (Upper)Upper Respiratory Tract Infection41374335Sinusitis11932Pharyngitis9773Rhinitis6532Epistaxis4211Skin and Appendage DisordersRash4222Urinary SystemUrinary Tract Infection7542Arthritis,coughing, and influenza-like symptoms occurred at rate of >=3% in theSPIRIVA HandiHaler treatment group, but were <1% in excessof the placebo group.Other reactions thatoccurred in the SPIRIVA HandiHaler group at frequency of 1% to 3% in theplacebo-controlled trials where the rates exceeded that in the placebo groupinclude: Body as 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 reactionsobserved 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 increasedwith age [see Use in Specific Populations (8.5) ].Two multicenter, 6-month,controlled studies evaluated SPIRIVA HandiHaler in patients with COPD. Theadverse reactions and the incidence rates were similar to those seen in the1-year controlled trials.4-Year TrialThe data described below reflect exposure to SPIRIVAHandiHaler in 5992 COPD patients in 4-year placebo-controlled trial. In thistrial, 2986 patients were treated with SPIRIVA HandiHaler at the recommendeddose of 18 mcg once day. The population had an age range from 40 to 88years, was 75% male, 90% Caucasian, and had COPD with mean pre-bronchodilatorFEV1 percent predicted of 40%. Patients with narrow-angleglaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstructionwere excluded from these trials. When the adverse reactions were analyzed witha frequency of >=3% in the SPIRIVA HandiHaler group where the rates in theSPIRIVA HandiHaler group exceeded placebo by >=1%, adverse reactions included (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%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).AdditionalAdverse ReactionsOther adverse reactions not previously listed that were reported more frequently inCOPD patients treated with SPIRIVA HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dryskin, skin infection, and joint swelling.. 6.2 Postmarketing Experience. Adversereactions have been identified during worldwide post-approval use of SPIRIVAHandiHaler. Because these reactions are reported voluntarily from populationof uncertain size, it is not always possible to reliably estimate theirfrequency or establish causal relationship to drug exposure. These adversereactions are: application site irritation (glossitis, mouth ulceration, andpharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinalobstruction including ileus paralytic, intraocular pressure increased, oralcandidiasis, palpitations, pruritus, tachycardia, throat irritation, andurticaria.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and Pharmacology. ReproductiveToxicology StudiesNo evidence of fetal structural alteration was observed in rats and rabbits atinhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively.These doses correspond to approximately 660 and times the RHDID on mg/m2 basis, respectively. However, in rats, fetalresorption, litter loss, decreases in the number of live pups at birth and themean pup weights, and delay in pup sexual maturation were observed atinhalation tiotropium doses of >=0.078 mg/kg (approximately 35 times theRHDID on mg/m2 basis). In rabbits, an increase in post-implantationloss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360times the RHDID on mg/m2 basis).Such effects were not observed at inhalation doses of 0.009 and up to 0.088mg/kg/day in rats and rabbits, respectively. These doses correspond toapproximately and 80 times the RHDID on mg/m2 basis, respectively. These dose multiples may beover-estimated due to difficulties in measuring deposited doses in animalinhalation studies.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Noevidence of tumorigenicity was observed in 104-week inhalation study in ratsat tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study infemale mice at doses up to 0.145 mg/kg/day, and in 101-week inhalationstudy in male mice at doses up to 0.002 mg/kg/day. These doses correspond to approximately25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on amg/m2 basis, respectively. These dose multiples may beover-estimated due to difficulties in measuring deposited doses in animalinhalation studies.Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in thefollowing assays: the bacterial gene mutation assay, the V79 Chinese hamstercell mutagenesis assay, the chromosomal aberration assays in human lymphocytes invitro and mouse micronucleus formation in vivo, and the unscheduledDNA synthesis in primary rat hepatocytes in vitro assay.In rats, decreases in the number of corpora lutea and the percentage of implantswere noted at inhalation tiotropium doses of 0.078 mg/kg/day or greater(approximately 35 times the RHDID on mg/m2 basis). No sucheffects were observed at 0.009 mg/kg/day (approximately times than theRHDID on mg/m2 basis). The fertility index, however, was notaffected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times theRHDID on mg/m2 basis). These dose multiples may be over-estimateddue to difficulties in measuring deposited doses in animal inhalation studies.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tiotropiumis long-acting, antimuscarinic agent, which is often referred to as ananticholinergic. It has similar affinity to the subtypes of muscarinicreceptors, M1 to M5. In the airways, it exhibitspharmacological effects through inhibition of M3-receptors at thesmooth muscle leading to bronchodilation. The competitive and reversible natureof antagonism was shown with human and animal origin receptors and isolatedorgan preparations. In preclinical in vitro as well as in vivostudies, prevention of methacholine-induced bronchoconstriction effects wasdose-dependent and lasted longer than 24 hours. The bronchodilation followinginhalation of tiotropium is predominantly site-specific effect.. 12.2 Pharmacodynamics. CardiovascularEffectsIn multicenter, randomized, double-blind trial that enrolled 198 patients withCOPD, the number of subjects with changes from baseline-corrected QT intervalof 30 to 60 msec was higher in the SPIRIVA HandiHaler group as compared withplacebo. This difference was apparent using both the Bazett (QTcB) [20 (20%)patients vs 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs (1%) patient] corrections of QT for heart rate. No patients in either group hadeither QTcB or QTcF of >500 msec. Other clinical studies with SPIRIVAHandiHaler did not detect an effect of the drug on QTc intervals. Theeffect of SPIRIVA HandiHaler on QT interval was also evaluated in randomized,placebo- and positive-controlled crossover study in 53 healthy volunteers.Subjects received SPIRIVA HandiHaler 18 mcg, 54 mcg (3 times the recommendeddose), or placebo for 12 days. ECG assessments were performed at baseline andthroughout the dosing interval following the first and last dose of studymedication. Relative to placebo, the maximum mean change from baseline instudy-specific QTc interval was 3.2 msec and 0.8 msec for SPIRIVA HandiHaler 18mcg and 54 mcg, respectively. No subject showed new onset of QTc >500 msecor QTc changes from baseline of >=60 msec.. 12.3 Pharmacokinetics. Tiotropiumis administered by dry powder inhalation. In common with other inhaled drugs,the majority of the delivered dose is deposited in the gastrointestinal tractand, to lesser extent, in the lung, the intended organ. Many of thepharmacokinetic data described below were obtained with higher doses thanrecommended for therapy.AbsorptionFollowing dry powder inhalation by young healthy volunteers, the absolute bioavailabilityof 19.5% suggests that the fraction reaching the lung is highly bioavailable.It is expected from the chemical structure of the compound (quaternary ammoniumcompound) that tiotropium is poorly absorbed from the gastrointestinal tract. Theeffect of food on tiotropiums bioavailability has not been studied. Oralsolutions of tiotropium have an absolute bioavailability of 2% to 3%.Maximum tiotropium plasma concentrations were observed minutes afterinhalation.DistributionTiotropium shows volume of distribution of 32 L/kg indicating that the drug bindsextensively to tissues. The human plasma protein binding for tiotropium is 72%.At steady state, peak tiotropium plasma levels in COPD patients were 17 to 19pg/mL when measured minutes after dry powder inhalation of an 18 mcg dose anddecreased in multi-compartmental manner. Steady-state trough plasmaconcentrations were to pg/mL. Local concentrations in the lungare not known, but the mode of administration suggests substantially higherconcentrations in the lung. Studies in rats have shown that tiotropium does notreadily penetrate the blood-brain barrier.MetabolismThe extent of metabolism appears to be small. This is evident from urinaryexcretion of 74% of unchanged substance after an intravenous dose to younghealthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to thealcohol N-methylscopine and dithienylglycolic acid, neither of whichbind to muscarinic receptors.Invitro experiments with human livermicrosomes and human hepatocytes suggest that fraction of the administereddose (74% of an intravenous dose is excreted unchanged in the urine, leaving25% for metabolism) is metabolized by cytochrome P450-dependent oxidation andsubsequent glutathione conjugation to variety of Phase II metabolites. Thisenzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such asquinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involvedin the metabolic pathway that is responsible for the elimination of smallpart of the administered dose. In vitro studies using human livermicrosomes showed that tiotropium in supra-therapeutic concentrations did notinhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.EliminationThe terminal elimination half-life of tiotropium was between and days followinginhalation. Total clearance was 880 mL/min after an intravenous dose in younghealthy volunteers with an inter-individual variability of 22%. Intravenouslyadministered tiotropium was mainly excreted unchanged in urine (74%). After drypowder inhalation, urinary excretion was 14% of the dose, the remainder beingmainly non-absorbed drug in the gut which was eliminated via the feces. Therenal clearance of tiotropium exceeds the creatinine clearance, indicatingactive secretion into the urine. After chronic once-daily inhalation by COPDpatients, pharmacokinetic steady state was reached after to weekswith no accumulation thereafter.Drug InteractionsAn interaction study with tiotropium (14.4 mcg intravenous infusion over 15minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg oncedaily was conducted. Concomitant administration of cimetidine with tiotropiumresulted in 20% increase in the AUC0-4h, 28% decrease in therenal clearance of tiotropium and no significant change in the Cmaxand amount excreted in urine over 96 hours. Co-administration of tiotropiumwith ranitidine did not affect the pharmacokinetics of tiotropium.SpecificPopulationsGeriatricPatientsAs expected for drugs predominantly excreted renally, advanced age was associatedwith decrease of tiotropium renal clearance (326 mL/min in COPD patients<58 years to 163 mL/min in COPD patients >70 years), which may beexplained by decreased renal function. Tiotropium excretion in urine afterinhalation decreased from 14% (young healthy volunteers) to about 7% (COPDpatients). Plasma concentrations were numerically increased with advancing agewithin COPD patients (43% increase in AUC0-4 after dry powderinhalation), which was not significant when considered in relation to inter-and intra-individual variability [see Dosage and Administration (2) andUse in Specific Populations (8.5) ].RenalImpairmentSince tiotropium is predominantly renally excreted, renal impairment was associatedwith increased plasma drug concentrations and reduced drug clearance after bothintravenous infusion and dry powder inhalation. Mild renal impairment (creatinineclearance of 50 to 80 mL/min), which is often seen in elderly patients,increased tiotropium plasma concentrations (39% increase in AUC0-4 afterintravenous infusion). In COPD patients with moderate to severe renalimpairment (creatinine clearance of <50 mL/min), the intravenousadministration of tiotropium resulted in doubling of the plasma concentrations(82% increase in AUC0-4), which was confirmed by plasmaconcentrations after dry powder inhalation. Patients with moderate to severerenal impairment (creatinine clearance of <=50 mL/min) treated withSPIRIVA HandiHaler should be monitored closely for anticholinergic side effects[see Dosage and Administration (2),Warnings and Precautions (5.4),and Use in Specific Populations (8.6) ].HepaticImpairmentThe effects of hepatic impairment on the pharmacokinetics of tiotropium were notstudied.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. Because clinical trialsare conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed inpractice.6-Month to 1-Year TrialsThedata described below reflect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA HandiHaler was studied in two 1-year placebo-controlled trials, two1-year active-controlled trials, and two 6-month placebo-controlled trials inpatients with COPD. In these trials, 1308 patientswere treated with SPIRIVA HandiHaler at the recommended dose of 18 mcgonce day. The population had an age ranging from 39 to 87 years with 65% to85% males, 95% Caucasian, and had COPD with mean pre-bronchodilator forcedexpiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, orsymptomatic prostatic hypertrophy or bladder outlet obstruction were excludedfrom these trials. An additional 6-month trial conducted in VeteransAffairs setting is not included in this safety database because only seriousadverse events were collected.Themost commonly reported adverse drug reaction was dry mouth. Dry mouth wasusually mild and often resolved during continued treatment. Other reactionsreported in individual patients and consistent with possible anticholinergiceffects included constipation, tachycardia, blurred vision, glaucoma (new onsetor worsening), dysuria, and urinary retention.Fourmulticenter, 1-year, placebo-controlled and active-controlled trials evaluatedSPIRIVA HandiHaler in patients with COPD. Table shows all adverse reactionsthat occurred with frequency of >=3% in the SPIRIVA HandiHalergroup in the 1-year placebo-controlled trials where the rates in the SPIRIVA HandiHalergroup exceeded placebo by >=1%. The frequency of corresponding reactions in theipratropium-controlled trials is included for comparison.Table Adverse Reactions(% Patients) in One-Year COPD Clinical TrialsBody System (Event)Placebo-Controlled TrialsIpratropium-Controlled Trials SPIRIVA(n 550)Placebo(n 371)SPIRIVA(n 356)Ipratropium(n 179)Body as WholeChest Pain (non-specific)7552Edema, Dependent5435Gastrointestinal System DisordersDry Mouth163126Dyspepsia6511Abdominal Pain5366Constipation4211Vomiting4212Musculoskeletal SystemMyalgia4343Resistance Mechanism DisordersInfection4313Moniliasis4232Respiratory System (Upper)Upper Respiratory Tract Infection41374335Sinusitis11932Pharyngitis9773Rhinitis6532Epistaxis4211Skin and Appendage DisordersRash4222Urinary SystemUrinary Tract Infection7542Arthritis,coughing, and influenza-like symptoms occurred at rate of >=3% in theSPIRIVA HandiHaler treatment group, but were <1% in excessof the placebo group.Other reactions thatoccurred in the SPIRIVA HandiHaler group at frequency of 1% to 3% in theplacebo-controlled trials where the rates exceeded that in the placebo groupinclude: Body as 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 reactionsobserved 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 increasedwith age [see Use in Specific Populations (8.5) ].Two multicenter, 6-month,controlled studies evaluated SPIRIVA HandiHaler in patients with COPD. Theadverse reactions and the incidence rates were similar to those seen in the1-year controlled trials.4-Year TrialThe data described below reflect exposure to SPIRIVAHandiHaler in 5992 COPD patients in 4-year placebo-controlled trial. In thistrial, 2986 patients were treated with SPIRIVA HandiHaler at the recommendeddose of 18 mcg once day. The population had an age range from 40 to 88years, was 75% male, 90% Caucasian, and had COPD with mean pre-bronchodilatorFEV1 percent predicted of 40%. Patients with narrow-angleglaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstructionwere excluded from these trials. When the adverse reactions were analyzed witha frequency of >=3% in the SPIRIVA HandiHaler group where the rates in theSPIRIVA HandiHaler group exceeded placebo by >=1%, adverse reactions included (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%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).AdditionalAdverse ReactionsOther adverse reactions not previously listed that were reported more frequently inCOPD patients treated with SPIRIVA HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dryskin, skin infection, and joint swelling.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. SPIRIVA HandiHaleris contraindicated in patients with hypersensitivityto ipratropium or tiotropium. In clinical trials and postmarketing experiencewith SPIRIVA HandiHaler, immediate hypersensitivity reactions, includingangioedema (including swelling of the lips, tongue, or throat), itching, orrash have been reported.. Hypersensitivity to ipratropium or tiotropium (4) Hypersensitivity to ipratropium or tiotropium (4).

DESCRIPTION SECTION.

11 DESCRIPTION. SPIRIVAHandiHaler consists of capsule dosage form containing dry powderformulation of tiotropium intended for oral inhalation only with the HandiHalerdevice.Eachlight green, hard gelatin SPIRIVA capsule contains 18 mcg tiotropium(equivalent to 22.5 mcg tiotropium bromide monohydrate) blended withlactose monohydrate (which may contain milk proteins) as the carrier.Thedry powder formulation within the SPIRIVA capsule is intended for oralinhalation only.Theactive component of SPIRIVA HandiHaler is tiotropium. The drug substance,tiotropium bromide monohydrate, is an anticholinergic with specificity formuscarinic receptors. It is chemically described as (1,2ss, 4ss, 5,7ss)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonanebromide monohydrate. It is synthetic, non-chiral, quaternary ammoniumcompound. Tiotropium bromide is white or yellowish white powder. It issparingly soluble in water and soluble in methanol.Thestructural formula is:Tiotropiumbromide (monohydrate) has molecular mass of 490.4 and molecular formula ofC19H22NO4S2Br H2O.The HandiHaler device is an inhalation device used to inhale the dry powdercontained in the SPIRIVA capsule. The dry powder is delivered from theHandiHaler device at flow rates as low as 20 L/min. Under standardized invitro testing, the HandiHaler device delivers mean of 10.4 mcgtiotropium when tested at flow rate of 39 L/min for 3.1 seconds (2 total).In study of 26 adult patients with COPD and severely compromised lungfunction [mean FEV1 1.02 (range 0.45 to 2.24 L); 37.6% ofpredicted (range 16% to 65%)], the median peak inspiratory flow (PIF) throughthe HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount ofdrug delivered to the lungs will vary depending on patient factors such asinspiratory flow and peak inspiratory flow through the HandiHaler device, whichmay vary from patient to patient, and may vary with the exposure time of the SPIRIVAcapsule outside the blister pack.. SPIRIVA Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION DO NOT SWALLOW SPIRIVA CAPSULESFOR USE WITH HANDIHALER DEVICE ONLYFOR ORAL INHALATION ONLYSPIRIVAcapsules must not be swallowed as the intended effects on the lungs will not beobtained. The contents of the SPIRIVA capsules are only for oral inhalation andshould only be used with the HandiHaler device [see Overdosage (10) ].Therecommended dose of SPIRIVA HandiHaler is two inhalations of the powder contentsof one SPIRIVA capsule, once-daily, with the HandiHaler device [see PatientCounseling Information (17.6)].For administration of SPIRIVA HandiHaler, SPIRIVA capsuleis placed into the center chamber of the HandiHaler device. The SPIRIVA capsuleis pierced by pressing and releasing the green piercing button on the side ofthe HandiHaler device. The tiotropium formulation is dispersed into the airstream when the patient inhales through the mouthpiece [see PatientCounseling Information (17.6)].Nodosage adjustment is required for geriatric, hepatically-impaired, orrenally-impaired patients. However, patients with moderate to severe renalimpairment given SPIRIVA HandiHaler should be monitored closely foranticholinergic effects [see Warnings and Precautions (5.6), Use in SpecificPopulations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3) ].. DO NOT swallow SPIRIVAcapsules (2) For Use with the HandiHalerDevice ONLY (2) For Oral Inhalation ONLY (2) Two inhalations of the powdercontents of single SPIRIVA capsule (18 mcg) once daily (2) Two inhalations of the powdercontents of single SPIRIVA capsule (18 mcg) once daily (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. SPIRIVAHandiHaler consists of SPIRIVA capsules and HandiHaler device. SPIRIVAcapsules contain 18 mcg dry powder formulation of tiotropium in alight green, hard gelatin capsule with TI 01 printed on one side and BoehringerIngelheim company logo on the other side. Supplied with HandiHaler device.. SPIRIVA capsules for oral inhalation: 18 mcg tiotropiumpowder, for use with HandiHaler device (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Not recommended for use with other anticholinergics sincethis has not been studied (7.2) 7.1 Sympathomimetics, Methylxanthines, Steroids. SPIRIVAHandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic(beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroidswithout increases in adverse drug reactions.. 7.2 Anticholinergics. Theco-administration of SPIRIVA HandiHaler with other anticholinergic-containingdrugs (e.g., ipratropium) has not been studied and is therefore notrecommended.. 7.3 Cimetidine, Ranitidine. Noclinically significant interaction occurred between tiotropium and cimetidineor ranitidine [see Clinical Pharmacology (12.3) ].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Ofthe total number of patients who received SPIRIVA HandiHaler in the 1-yearclinical trials, 426 were <65 years, 375 were 65 to 74 years, and105 were >=75 years of age. Within each age subgroup, there wereno differences between the proportion of patients with adverse events in theSPIRIVA HandiHaler and the comparator groups for most events. Dry mouthincreased with age in the SPIRIVA HandiHaler group (differences from placebowere 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). higherfrequency of constipation and urinary tract infections with increasing age wasobserved in the SPIRIVA HandiHaler group in the placebo-controlled studies. Thedifferences from placebo for constipation were 0%, 1.8%, and 7.8% for each ofthe age groups. The differences from placebo for urinary tract infections were-0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observedamong these groups. Based on available data, no adjustment of SPIRIVA HandiHalerdosage in geriatric patients is warranted [see Clinical Pharmacology (12.3) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. SPIRIVAHandiHaler consists of SPIRIVA capsules and the HandiHaler device. SPIRIVA capsulescontain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheimcompany logo on the SPIRIVA capsule cap and TI 01 on the SPIRIVA capsule body,or vice versa.TheHandiHaler device is gray colored with green piercing button. It is imprintedwith SPIRIVA HandiHaler (tiotropium bromide inhalation powder), the BoehringerIngelheim company logo, and the Pfizer company logo. It is also imprinted toindicate that SPIRIVA capsules should not be stored in the HandiHaler deviceand that the HandiHaler device is only to be used with SPIRIVA capsules.SPIRIVAcapsules are packaged in an aluminum/aluminum blister card and joined along aperforated-cut line. SPIRIVA capsules should always be stored in the blisterand only removed immediately before use. The drug should be used immediatelyafter the packaging over an individual SPIRIVA capsule is opened.Thefollowing packages are available:carton containing SPIRIVAcapsules (5 unit-dose blister cards) and HandiHaler inhalation device (NDC 54868-5109-0)carton containing 90 SPIRIVAcapsules (9 unit-dose blister cards) and HandiHaler inhalation device (NDC 54868-5109-1)StorageStoreat 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].The SPIRIVA capsules should not be exposed to extreme temperature or moisture. Donot store SPIRIVA capsules in the HandiHaler device.. carton containing SPIRIVAcapsules (5 unit-dose blister cards) and HandiHaler inhalation device (NDC 54868-5109-0). carton containing 90 SPIRIVAcapsules (9 unit-dose blister cards) and HandiHaler inhalation device (NDC 54868-5109-1).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. SPIRIVA HandiHaler (tiotropium bromide inhalationpowder) is indicated for the long-term, once-daily, maintenance treatment ofbronchospasm associated with chronic obstructive pulmonary disease (COPD),including chronic bronchitis and emphysema. SPIRIVA HandiHaler is indicated toreduce exacerbations in COPD patients.. SPIRIVA HandiHaler is ananticholinergic indicated for the long-term, once-daily, maintenance treatmentof bronchospasm associated with chronic obstructive pulmonary disease (COPD), andfor reducing COPD exacerbations (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved Patient Labeling (17.6) 17.1 Instructions for Administering SPIRIVA HandiHaler. Itis important for patients to understand how to correctly administer SPIRIVAcapsules using the HandiHaler device [see Patient Counseling Information(17.6) ]. Patients should be instructed that SPIRIVA capsules should only beadministered via the HandiHaler device and the HandiHaler device should not beused for administering other medications. The contents of SPIRIVA capsulesare for oral inhalation only and must not be swallowed.SPIRIVAcapsules should always be stored in sealed blisters. Only one SPIRIVA capsule shouldbe removed immediately before use or its effectiveness may be reduced.Additional SPIRIVA capsules that are exposed to air (i.e., not intended forimmediate use) should be discarded.. 17.2 Paradoxical Bronchospasm. Patientsshould be informed that SPIRIVA HandiHaler can produce paradoxicalbronchospasm. If paradoxical bronchospasm occurs, patients should discontinueSPIRIVA HandiHaler.. 17.3 Urinary Retention. Difficultypassing urine and dysuria may be symptoms of new or worsening prostatichyperplasia or bladder outlet obstruction. Patients should be instructed toconsult physician immediately should any of these signs or symptoms develop.. 17.4 Visual Effects. Eyepain or discomfort, blurred vision, visual halos or colored images inassociation with red eyes from conjunctival congestion and corneal edema may besigns of acute narrow-angle glaucoma. Patients should be told to consult aphysician immediately should any of these signs and symptoms develop. Mioticeye drops alone are not considered to be effective treatment.Patientsshould be told that care must be taken not to allow the powder to enter intothe eyes as this may cause blurring of vision and pupil dilation.. 17.5 Acute Exacerbation. Patientsshould understand that SPIRIVA HandiHaler is once-daily maintenancebronchodilator and should not be used for immediate relief of breathingproblems (i.e., as rescue medication).. 17.6 FDA-approved Patient Labeling. PatientInformation and Patients Instructions for Use are supplied as tear-off leafletsfollowing the full prescribing information and should be dispensed with eachnew prescription and refill.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USAMarketed by:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAandPfizer IncNew York, NY 10017 USALicensed from:Boehringer Ingelheim International GmbHAddress medical inquiries to: (800)542-6257 or (800) 459-9906 TTY.SPIRIVA(R) and HandiHaler(R) are registered trademarks and are used under license from Boehringer Ingelheim InternationalGmbH.(C)Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDSPIRIVA(R) (tiotropium bromide inhalation powder) is covered byU.S. Patent Nos. RE38,912, RE39,820, 5,478,578, 6,777,423, 6,908,928, 7,070,800,and 7,309,707 with other patents pending. The HandiHaler(R) inhalationdevice is covered by U.S. Design Patent No. D355,029 with other patentspending.Rev:December 2009IT1600WL160910004551/0765626-08Relabeling of Additional Barcode by:Physicians Total Care, Inc.Tulsa, OK 74146.

LABOR & DELIVERY SECTION.

8.2 Labor and Delivery. Thesafety and effectiveness of SPIRIVA HandiHaler has not been studied duringlabor and delivery.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tiotropiumis long-acting, antimuscarinic agent, which is often referred to as ananticholinergic. It has similar affinity to the subtypes of muscarinicreceptors, M1 to M5. In the airways, it exhibitspharmacological effects through inhibition of M3-receptors at thesmooth muscle leading to bronchodilation. The competitive and reversible natureof antagonism was shown with human and animal origin receptors and isolatedorgan preparations. In preclinical in vitro as well as in vivostudies, prevention of methacholine-induced bronchoconstriction effects wasdose-dependent and lasted longer than 24 hours. The bronchodilation followinginhalation of tiotropium is predominantly site-specific effect.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Noevidence of tumorigenicity was observed in 104-week inhalation study in ratsat tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study infemale mice at doses up to 0.145 mg/kg/day, and in 101-week inhalationstudy in male mice at doses up to 0.002 mg/kg/day. These doses correspond to approximately25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on amg/m2 basis, respectively. These dose multiples may beover-estimated due to difficulties in measuring deposited doses in animalinhalation studies.Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in thefollowing assays: the bacterial gene mutation assay, the V79 Chinese hamstercell mutagenesis assay, the chromosomal aberration assays in human lymphocytes invitro and mouse micronucleus formation in vivo, and the unscheduledDNA synthesis in primary rat hepatocytes in vitro assay.In rats, decreases in the number of corpora lutea and the percentage of implantswere noted at inhalation tiotropium doses of 0.078 mg/kg/day or greater(approximately 35 times the RHDID on mg/m2 basis). No sucheffects were observed at 0.009 mg/kg/day (approximately times than theRHDID on mg/m2 basis). The fertility index, however, was notaffected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times theRHDID on mg/m2 basis). These dose multiples may be over-estimateddue to difficulties in measuring deposited doses in animal inhalation studies.. 13.2 Animal Toxicology and Pharmacology. ReproductiveToxicology StudiesNo evidence of fetal structural alteration was observed in rats and rabbits atinhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively.These doses correspond to approximately 660 and times the RHDID on mg/m2 basis, respectively. However, in rats, fetalresorption, litter loss, decreases in the number of live pups at birth and themean pup weights, and delay in pup sexual maturation were observed atinhalation tiotropium doses of >=0.078 mg/kg (approximately 35 times theRHDID on mg/m2 basis). In rabbits, an increase in post-implantationloss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360times the RHDID on mg/m2 basis).Such effects were not observed at inhalation doses of 0.009 and up to 0.088mg/kg/day in rats and rabbits, respectively. These doses correspond toapproximately and 80 times the RHDID on mg/m2 basis, respectively. These dose multiples may beover-estimated due to difficulties in measuring deposited doses in animalinhalation studies.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Clinicaldata from nursing women exposed to tiotropium are not available. Based onlactating rodent studies, tiotropium is excreted into breast milk. It is notknown whether tiotropium is excreted in human milk, but because many drugs areexcreted in human milk and given these findings in rats, caution should beexercised if SPIRIVA HandiHaler is administered to nursing woman.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Highdoses of tiotropium may lead to anticholinergic signs and symptoms. However,there were no systemic anticholinergic adverse effects following singleinhaled dose of up to 282 mcg tiotropium in healthy volunteers. In study of12 healthy volunteers, bilateral conjunctivitis and dry mouth were seenfollowing repeated once-daily inhalation of 141 mcg of tiotropium.Accidental IngestionAcute intoxicationby inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is notwell-absorbed systemically.Acase of overdose has been reported from postmarketing experience. femalepatient was reported to have inhaled 30 capsules over 2.5 day period, anddeveloped altered mental status, tremors, abdominal pain, and severeconstipation. The patient was hospitalized, SPIRIVA HandiHaler wasdiscontinued, and the constipation was treated with an enema. The patientrecovered and was discharged on the same day.Nomortality 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 850 times the recommended human daily inhalation dose on mg/m2basis, respectively. These dose multiples may be over-estimated due todifficulties in measuring deposited doses in animal inhalation studies.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

SPIRIVA HandiHaler30 capsules (5 blister cards)1 HandiHaler Inhalation Device. SPIRIVA HandiHaler 30 capsules.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. SPIRIVAHandiHaler is approved for use in the maintenance treatment of bronchospasmassociated with COPD and for the reduction of COPD exacerbations. COPD does notnormally occur in children. The safety and effectiveness of SPIRIVA HandiHaler inpediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. CardiovascularEffectsIn multicenter, randomized, double-blind trial that enrolled 198 patients withCOPD, the number of subjects with changes from baseline-corrected QT intervalof 30 to 60 msec was higher in the SPIRIVA HandiHaler group as compared withplacebo. This difference was apparent using both the Bazett (QTcB) [20 (20%)patients vs 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs (1%) patient] corrections of QT for heart rate. No patients in either group hadeither QTcB or QTcF of >500 msec. Other clinical studies with SPIRIVAHandiHaler did not detect an effect of the drug on QTc intervals. Theeffect of SPIRIVA HandiHaler on QT interval was also evaluated in randomized,placebo- and positive-controlled crossover study in 53 healthy volunteers.Subjects received SPIRIVA HandiHaler 18 mcg, 54 mcg (3 times the recommendeddose), or placebo for 12 days. ECG assessments were performed at baseline andthroughout the dosing interval following the first and last dose of studymedication. Relative to placebo, the maximum mean change from baseline instudy-specific QTc interval was 3.2 msec and 0.8 msec for SPIRIVA HandiHaler 18mcg and 54 mcg, respectively. No subject showed new onset of QTc >500 msecor QTc changes from baseline of >=60 msec.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Tiotropiumis administered by dry powder inhalation. In common with other inhaled drugs,the majority of the delivered dose is deposited in the gastrointestinal tractand, to lesser extent, in the lung, the intended organ. Many of thepharmacokinetic data described below were obtained with higher doses thanrecommended for therapy.AbsorptionFollowing dry powder inhalation by young healthy volunteers, the absolute bioavailabilityof 19.5% suggests that the fraction reaching the lung is highly bioavailable.It is expected from the chemical structure of the compound (quaternary ammoniumcompound) that tiotropium is poorly absorbed from the gastrointestinal tract. Theeffect of food on tiotropiums bioavailability has not been studied. Oralsolutions of tiotropium have an absolute bioavailability of 2% to 3%.Maximum tiotropium plasma concentrations were observed minutes afterinhalation.DistributionTiotropium shows volume of distribution of 32 L/kg indicating that the drug bindsextensively to tissues. The human plasma protein binding for tiotropium is 72%.At steady state, peak tiotropium plasma levels in COPD patients were 17 to 19pg/mL when measured minutes after dry powder inhalation of an 18 mcg dose anddecreased in multi-compartmental manner. Steady-state trough plasmaconcentrations were to pg/mL. Local concentrations in the lungare not known, but the mode of administration suggests substantially higherconcentrations in the lung. Studies in rats have shown that tiotropium does notreadily penetrate the blood-brain barrier.MetabolismThe extent of metabolism appears to be small. This is evident from urinaryexcretion of 74% of unchanged substance after an intravenous dose to younghealthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to thealcohol N-methylscopine and dithienylglycolic acid, neither of whichbind to muscarinic receptors.Invitro experiments with human livermicrosomes and human hepatocytes suggest that fraction of the administereddose (74% of an intravenous dose is excreted unchanged in the urine, leaving25% for metabolism) is metabolized by cytochrome P450-dependent oxidation andsubsequent glutathione conjugation to variety of Phase II metabolites. Thisenzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such asquinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involvedin the metabolic pathway that is responsible for the elimination of smallpart of the administered dose. In vitro studies using human livermicrosomes showed that tiotropium in supra-therapeutic concentrations did notinhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.EliminationThe terminal elimination half-life of tiotropium was between and days followinginhalation. Total clearance was 880 mL/min after an intravenous dose in younghealthy volunteers with an inter-individual variability of 22%. Intravenouslyadministered tiotropium was mainly excreted unchanged in urine (74%). After drypowder inhalation, urinary excretion was 14% of the dose, the remainder beingmainly non-absorbed drug in the gut which was eliminated via the feces. Therenal clearance of tiotropium exceeds the creatinine clearance, indicatingactive secretion into the urine. After chronic once-daily inhalation by COPDpatients, pharmacokinetic steady state was reached after to weekswith no accumulation thereafter.Drug InteractionsAn interaction study with tiotropium (14.4 mcg intravenous infusion over 15minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg oncedaily was conducted. Concomitant administration of cimetidine with tiotropiumresulted in 20% increase in the AUC0-4h, 28% decrease in therenal clearance of tiotropium and no significant change in the Cmaxand amount excreted in urine over 96 hours. Co-administration of tiotropiumwith ranitidine did not affect the pharmacokinetics of tiotropium.SpecificPopulationsGeriatricPatientsAs expected for drugs predominantly excreted renally, advanced age was associatedwith decrease of tiotropium renal clearance (326 mL/min in COPD patients<58 years to 163 mL/min in COPD patients >70 years), which may beexplained by decreased renal function. Tiotropium excretion in urine afterinhalation decreased from 14% (young healthy volunteers) to about 7% (COPDpatients). Plasma concentrations were numerically increased with advancing agewithin COPD patients (43% increase in AUC0-4 after dry powderinhalation), which was not significant when considered in relation to inter-and intra-individual variability [see Dosage and Administration (2) andUse in Specific Populations (8.5) ].RenalImpairmentSince tiotropium is predominantly renally excreted, renal impairment was associatedwith increased plasma drug concentrations and reduced drug clearance after bothintravenous infusion and dry powder inhalation. Mild renal impairment (creatinineclearance of 50 to 80 mL/min), which is often seen in elderly patients,increased tiotropium plasma concentrations (39% increase in AUC0-4 afterintravenous infusion). In COPD patients with moderate to severe renalimpairment (creatinine clearance of <50 mL/min), the intravenousadministration of tiotropium resulted in doubling of the plasma concentrations(82% increase in AUC0-4), which was confirmed by plasmaconcentrations after dry powder inhalation. Patients with moderate to severerenal impairment (creatinine clearance of <=50 mL/min) treated withSPIRIVA HandiHaler should be monitored closely for anticholinergic side effects[see Dosage and Administration (2),Warnings and Precautions (5.4),and Use in Specific Populations (8.6) ].HepaticImpairmentThe effects of hepatic impairment on the pharmacokinetics of tiotropium were notstudied.

PREGNANCY SECTION.

8.1 Pregnancy. TeratogenicEffects, Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women. SPIRIVAHandiHaler should be used during pregnancy only if the potential benefitjustifies the potential risk to the fetus.Noevidence of structural alterations was observed in rats and rabbits atinhalation tiotropium doses of up to approximately 660 and times therecommended human daily inhalation dose (RHDID) on 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 adelay in pup sexual maturation at inhalation tiotropium doses of approximately35 times the RHDID on mg/m2 basis. In rabbits, tiotropium caused anincrease in post-implantation loss at an inhalation dose of approximately 360times the RHDID on mg/m2 basis. Such effects were not observed atinhalation doses of approximately and 80 times the RHDID on mg/m2basis, respectively. These dose multiples may be over-estimated due todifficulties in measuring deposited doses in animal inhalation studies.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 12/2009Dosage and Administration (2) 12/2009Contraindications (4) 12/2009Warnings and Precautions, Immediate Hypersensitivity Reactions (5.2) 12/2009 Worsening of Narrow-Angle Glaucoma (5.4) 12/2009 Worsening of Urinary Retention (5.5) 12/2009 Renal Impairment (5.6) 12/2009.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationSPIRIVA(R) (speh REE vah) HandiHaler(R) (tiotropium bromide inhalation powder)Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the HandiHaler device. SPIRIVA HandiHaler should only be inhaled by 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 HandiHalerSPIRIVA HandiHaler is prescription medicine that you use one time every day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD). 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 also reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). 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 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.SPIRIVA HandiHaler has not been studied in children.Who should not take SPIRIVA HandiHalerDo not use SPIRIVA HandiHaler if you:are allergic to tiotropium. See the end of this leaflet for complete list of ingredients.have had an allergic reaction to ipratropium (Atrovent(R)).Allergic reactions may include itching, rash, or swelling of the lips, tongue, or throat (trouble swallowing).What should tell my doctor before using SPIRIVA HandiHalerBefore 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 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 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 list of your medicines with you to show your doctor and pharmacist when you get new medicine. How should take SPIRIVA HandiHalerUse SPIRIVA HandiHaler exactly as prescribed. Use SPIRIVA HandiHaler one time every day. Read the Patients 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 medicineSPIRIVA HandiHaler comes as powder in SPIRIVA capsule that fits the HandiHaler device. Each SPIRIVA capsule, containing only 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 complete dose of SPIRIVA HandiHaler by breathing in the powder by mouth two times, using the HandiHaler device (take inhalations from one SPIRIVA capsule). See the Patients 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 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 poison control center.What should avoid while using SPIRIVA HandiHalerDo 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.What are the possible side effects of SPIRIVA HandiHalerSPIRIVA HandiHaler can cause serious side effects. If you get any of the following side effects, stop taking SPIRIVA HandiHaler and get medical help right away.Allergic reaction. Symptoms may include: itching, rash, swelling of the lips, tongue, or throat (trouble swallowing).Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.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.New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination.Other side effects with SPIRIVA HandiHaler include:upper respiratory tract infectiondry mouthsinus infectionsore throatnon-specific chest painurinary tract infectionindigestionrunny noseconstipationincreased heart rateblurred visionThese 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 store SPIRIVA HandiHalerDo not store SPIRIVA capsules in the HandiHaler device.Store SPIRIVA capsules in the sealed blister package at room temperature between 68F-77F (20-25C).Keep SPIRIVA capsules away from heat and cold (do not freeze).Store SPIRIVA capsules in 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 HandiHalerMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use SPIRIVA HandiHaler for 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 more information about SPIRIVA HandiHaler, you may call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.What are the ingredients in SPIRIVA HandiHalerActive ingredient: tiotropiumInactive ingredient: lactose monohydrateWhat is COPD (Chronic Obstructive Pulmonary Disease) COPD is 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.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA Marketed by:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAandPfizer IncNew York, NY 10017 USA Licensed from:Boehringer Ingelheim International GmbHSPIRIVA(R) and HandiHaler(R) are registered trademarks and are used under license from Boehringer Ingelheim International GmbH.(C)Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED Rev: December 2009IT1600WL160910004551/0765626-08Patients Instructions for UseSPIRIVA HandiHaler(R) (tiotropium bromide inhalation powder)Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the HandiHaler device. SPIRIVA HandiHaler should only be inhaled through your mouth (oral inhalation).First read the Patient Information that comes with SPIRIVA HandiHaler for important information about using SPIRIVA HandiHaler. Read these Patients Instructions for Use before you start to use SPIRIVA HandiHaler and each time you refill your prescription. There may be new information.For more information, ask your doctor or pharmacist.SPIRIVA HandiHaler comes with SPIRIVA capsules and HandiHaler device. The HandiHaler device is an inhalation device that is for use only with SPIRIVA capsules. Do not use the HandiHaler device to take any other medicine.Becoming familiar with SPIRIVA HandiHaler: Remove the HandiHaler device from the pouch and become familiar with its components. (Figure A) dust capmouthpiecemouthpiece ridgebasegreen piercing buttoncenter chamberair intake vents Each SPIRIVA capsule is packaged in blister. Each blister can be separated from the blister card by tearing along the perforation. (Figure B)Do not open the SPIRIVA capsule before you insert it into the HandiHaler device. If you open the SPIRIVA capsule, it may not work. Each SPIRIVA capsule contains only small amount of powder. (Figure C) This is one full dose. The product was designed this way. How do inhale the contents of the SPIRIVA capsule using the HandiHaler deviceTaking your dose of medicine using the HandiHaler device has four main steps:Open the HandiHaler device and the blisterInsert the SPIRIVA capsulePress the green piercing buttonBreathe in (inhale) your medicine(See below for details) Opening the HandiHaler device: 1. Open the dust cap by pressing the green piercing button. (Figure 1)Pull the dust cap upwards to expose the mouthpiece. (Figure 2)Open the mouthpiece by pulling the mouthpiece ridge upwards away from the base. (Figure 3)Removing SPIRIVA capsule:Before removing SPIRIVA capsule from the blister, separate one of the blisters from the blister card by tearing along the perforation. (Figure 4) Do not swallow SPIRIVA capsules. Always store SPIRIVA capsules in the sealed blisters. Remove only one SPIRIVA capsule from the blister right before use. Do not store SPIRIVA capsules in the HandiHaler device. Inhale the contents of the SPIRIVA capsule using the HandiHaler device right away after the blister packaging of an individual SPIRIVA capsule is opened, or else it may not work as well.Right before you are ready to use your SPIRIVA HandiHaler: Bend back and forth one of the corners of the blister that has an arrow and then with your finger separate the aluminum foil layers. Carefully peel back the printed foil until you can see the whole SPIRIVA capsule. (Figure 5) Turn the blister upside down and tip the SPIRIVA capsule out, tapping the back of the blister, if needed. Do not cut the foil or use sharp instruments to take out the SPIRIVA capsule from the blister. If more SPIRIVA capsules are opened to air, they should not be used and should be thrown away.Inserting the SPIRIVA capsule into the HandiHaler device:2. Insert (put) the SPIRIVA capsule in the center chamber of the HandiHaler device. It does not matter which end of the SPIRIVA capsule you put in the chamber. (Figure 6)Close the mouthpiece until you hear click, but leave the dust cap open. (Figure 7) Be sure that you have the mouthpiece sitting firmly against the gray base.Taking your dose using the HandiHaler device:Hold the HandiHaler device with the mouthpiece upright. It is important that you hold the HandiHaler device in an upright position (Figure 8) when pressing the green piercing button. 3. Press the green piercing button until it is flat (flush) against the base, and release. This is how you make holes in the SPIRIVA capsule so that you get the medicine when you breathe in. Do not press the green button more than one time.Breathe out completely. (Figure 9) Important: Do not breathe (exhale) into the mouthpiece of the HandiHaler device at any time. 4. Breathe in (inhale)Hold the HandiHaler device by the gray base. Do not block the air intake vents. Raise the HandiHaler device to your mouth and close your lips tightly around the mouthpiece. Keep your head in an upright position. The HandiHaler device should be in horizontal position. (Figure 10)Breathe in slowly and deeply so that you hear or feel the SPIRIVA capsule vibrate. Breathe in until your lungs are full. Hold your breath as long as is comfortable and at the same time take the HandiHaler device out of your mouth. Breathe normally again. To make sure you get the full dose, you must breathe out completely, and inhale again as in step above (Figure 10). Do not press the green piercing button again. If you do not hear or feel the SPIRIVA capsule vibrate, do not press the green piercing button again. Instead, hold the HandiHaler device in an upright position and tap the HandiHaler device gently on table. (Figure 11) Check to see that the mouthpiece is completely closed. Then, breathe in again slowly and deeply. If you still do not hear or feel the SPIRIVA capsule vibrate after repeating the above steps, throw away the SPIRIVA capsule. Open the base by lifting the green piercing button and check the center chamber for pieces of the SPIRIVA capsule (SPIRIVA capsule fragments). SPIRIVA capsule fragments in the center chamber can cause SPIRIVA capsule not to vibrate. Turn the HandiHaler device upside down and gently tap to remove the SPIRIVA capsule fragments. Call your doctor for instructions.After you finish taking your daily dose of SPIRIVA HandiHaler, open the mouthpiece again. Tip out the used SPIRIVA capsule and throw it away. (Figure 12)Close the mouthpiece and dust cap for storage of your HandiHaler device. (Figure 13) Do not store used or unused SPIRIVA capsules in the HandiHaler device.When and how should clean my HandiHaler deviceClean the HandiHaler device one time each month or as needed. (Figure 14)Open the dust cap and mouthpiece.Open the base by lifting the green piercing button. Look at the center chamber for SPIRIVA capsule fragments or powder residue.Rinse the HandiHaler device with warm water. Check that any powder buildup or SPIRIVA capsule fragments are removed.Do not use cleaning agents or detergents. Do not place the HandiHaler device in the dishwasher for cleaning.Dry the HandiHaler device well by tipping the excess water out on paper towel. Air-dry afterwards, leaving the dust cap, mouthpiece, and base open.Do not use hair dryer to dry the HandiHaler device.It takes 24 hours to air dry, so clean the HandiHaler device right after you use it so that it will be ready for your next dose.Do not use the HandiHaler device when it is wet. If needed, you may clean the outside of the mouthpiece with clean damp cloth.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USAMarketed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USAandPfizer IncNew York, NY 10017 USALicensed from:Boehringer Ingelheim International GmbHSPIRIVA(R) and HandiHaler(R) are registered trademarks and are used under license from Boehringer Ingelheim International GmbH(C)Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDRev: December 2009IT1600WL160910004551/0765626-08. are allergic to tiotropium. See the end of this leaflet for complete list of ingredients.. have had an allergic reaction to ipratropium (Atrovent(R)).. have kidney problems.. have glaucoma. SPIRIVA HandiHaler may make your glaucoma worse.. have an enlarged prostate, problems passing urine, or 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 severe allergy to milk proteins. Ask your doctor if you are not sure.. Use SPIRIVA HandiHaler exactly as prescribed. Use SPIRIVA HandiHaler one time every day. Read the Patients 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 powder in SPIRIVA capsule that fits the HandiHaler device. Each SPIRIVA capsule, containing only 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 complete dose of SPIRIVA HandiHaler by breathing in the powder by mouth two times, using the HandiHaler device (take inhalations from one SPIRIVA capsule). See the Patients 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 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 poison control center.. Allergic reaction. Symptoms may include: itching, rash, swelling of the lips, tongue, or throat (trouble swallowing).. Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.. 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.. New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include: difficulty passing urine, painful urination.. 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. Do not store SPIRIVA capsules in the HandiHaler device.. Store SPIRIVA capsules in the sealed blister package at room temperature between 68F-77F (20-25C).. Keep SPIRIVA capsules away from heat and cold (do not freeze).. Store SPIRIVA capsules in dry place. Throw away any unused SPIRIVA capsules that have been open to air.. dust cap. mouthpiece. mouthpiece ridge. base. green piercing button. center chamber. air intake vents. Open the HandiHaler device and the blister. Insert the SPIRIVA capsule. Press the green piercing button. Breathe in (inhale) your medicine. Hold the HandiHaler device by the gray base. Do not block the air intake vents. Raise the HandiHaler device to your mouth and close your lips tightly around the mouthpiece. Keep your head in an upright position. The HandiHaler device should be in horizontal position. (Figure 10). Breathe in slowly and deeply so that you hear or feel the SPIRIVA capsule vibrate. Breathe in until your lungs are full. Hold your breath as long as is comfortable and at the same time take the HandiHaler device out of your mouth. Breathe normally again. Open the dust cap and mouthpiece.. Open the base by lifting the green piercing button. Look at the center chamber for SPIRIVA capsule fragments or powder residue.. Rinse the HandiHaler device with warm water. Check that any powder buildup or SPIRIVA capsule fragments are removed.. Do not use cleaning agents or detergents. Do not place the HandiHaler device in the dishwasher for cleaning.. Dry the HandiHaler device well by tipping the excess water out on paper towel. Air-dry afterwards, leaving the dust cap, mouthpiece, and base open.. Do not use hair dryer to dry the HandiHaler device.. It takes 24 hours to air dry, so clean the HandiHaler device right after you use it so that it will be ready for your next dose.. Do not use the HandiHaler device when it is wet. If needed, you may clean the outside of the mouthpiece with clean damp cloth.. Instructions for SPIRIVA. Instructions for SPIRIVA. Figure A. Figure B. Figure C. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 11. Figure 12. Figure 13. Figure 14.

SPL UNCLASSIFIED SECTION.

5.1 Not for Acute Use. SPIRIVAHandiHaler is intended as once-daily maintenance treatment for COPD and isnot indicated for the initial treatment of acute episodes of bronchospasm (i.e.,rescue therapy).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Patients with moderate to severe renal impairment shouldbe monitored closely for potential anticholinergic side effects (2, 8.6) 8.1 Pregnancy. TeratogenicEffects, Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women. SPIRIVAHandiHaler should be used during pregnancy only if the potential benefitjustifies the potential risk to the fetus.Noevidence of structural alterations was observed in rats and rabbits atinhalation tiotropium doses of up to approximately 660 and times therecommended human daily inhalation dose (RHDID) on 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 adelay in pup sexual maturation at inhalation tiotropium doses of approximately35 times the RHDID on mg/m2 basis. In rabbits, tiotropium caused anincrease in post-implantation loss at an inhalation dose of approximately 360times the RHDID on mg/m2 basis. Such effects were not observed atinhalation doses of approximately and 80 times the RHDID on mg/m2basis, respectively. These dose multiples may be over-estimated due todifficulties in measuring deposited doses in animal inhalation studies.. 8.2 Labor and Delivery. Thesafety and effectiveness of SPIRIVA HandiHaler has not been studied duringlabor and delivery.. 8.3 Nursing Mothers. Clinicaldata from nursing women exposed to tiotropium are not available. Based onlactating rodent studies, tiotropium is excreted into breast milk. It is notknown whether tiotropium is excreted in human milk, but because many drugs areexcreted in human milk and given these findings in rats, caution should beexercised if SPIRIVA HandiHaler is administered to nursing woman.. 8.4 Pediatric Use. SPIRIVAHandiHaler is approved for use in the maintenance treatment of bronchospasmassociated with COPD and for the reduction of COPD exacerbations. COPD does notnormally occur in children. The safety and effectiveness of SPIRIVA HandiHaler inpediatric patients have not been established.. 8.5 Geriatric Use. Ofthe total number of patients who received SPIRIVA HandiHaler in the 1-yearclinical trials, 426 were <65 years, 375 were 65 to 74 years, and105 were >=75 years of age. Within each age subgroup, there wereno differences between the proportion of patients with adverse events in theSPIRIVA HandiHaler and the comparator groups for most events. Dry mouthincreased with age in the SPIRIVA HandiHaler group (differences from placebowere 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). higherfrequency of constipation and urinary tract infections with increasing age wasobserved in the SPIRIVA HandiHaler group in the placebo-controlled studies. Thedifferences from placebo for constipation were 0%, 1.8%, and 7.8% for each ofthe age groups. The differences from placebo for urinary tract infections were-0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observedamong these groups. Based on available data, no adjustment of SPIRIVA HandiHalerdosage in geriatric patients is warranted [see Clinical Pharmacology (12.3) ].. 8.6 Renal Impairment. Patientswith moderate to severe renal impairment (creatinine clearance of <=50mL/min) treated with SPIRIVA HandiHaler should be monitored closely foranticholinergic side effects [see Dosage and Administration (2), Warningsand Precautions (5.4), and Clinical Pharmacology (12.3) ].. 8.7 Hepatic Impairment. Theeffects of hepatic impairment on the pharmacokinetics of tiotropium were notstudied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Not for acute use: Not for use as arescue medication (5.1) Immediate hypersensitivityreactions: Discontinue SPIRIVA HandiHaler at once and consider alternatives ifimmediate hypersensitivity reactions, including angioedema, occur. Use withcaution in patients with severe hypersensitivity to milk proteins. (5.2) Paradoxical bronchospasm: DiscontinueSPIRIVA HandiHaler and consider other treatments if paradoxical bronchospasmoccurs (5.3) Worsening of narrow-angle glaucomamay occur. Use with caution in patients with narrow-angle glaucoma andinstruct patients to consult physician immediately if this occurs. (5.4) Worsening of urinary retention mayoccur. Use with caution in patients with prostatic hyperplasia or bladder-neckobstruction and instruct patients to consult physician immediately if thisoccurs. (5.5) Not for acute use: Not for use as arescue medication (5.1) Immediate hypersensitivityreactions: Discontinue SPIRIVA HandiHaler at once and consider alternatives ifimmediate hypersensitivity reactions, including angioedema, occur. Use withcaution in patients with severe hypersensitivity to milk proteins. (5.2) Paradoxical bronchospasm: DiscontinueSPIRIVA HandiHaler and consider other treatments if paradoxical bronchospasmoccurs (5.3) Worsening of narrow-angle glaucomamay occur. Use with caution in patients with narrow-angle glaucoma andinstruct patients to consult physician immediately if this occurs. (5.4) Worsening of urinary retention mayoccur. Use with caution in patients with prostatic hyperplasia or bladder-neckobstruction and instruct patients to consult physician immediately if thisoccurs. (5.5) 5.1 Not for Acute Use. SPIRIVAHandiHaler is intended as once-daily maintenance treatment for COPD and isnot indicated for the initial treatment of acute episodes of bronchospasm (i.e.,rescue therapy).. 5.2 Immediate Hypersensitivity Reactions. Immediate hypersensitivity reactions, includingangioedema (including swelling of the lips, tongue, or throat), itching, orrash may occur after administration of SPIRIVA HandiHaler. If such reactionoccurs, therapy with SPIRIVA HandiHaler should be stopped at once andalternative treatments should be considered. Given the similar structuralformula of atropine to tiotropium, patients with history of hypersensitivityreactions to atropine should be closely monitored for similar hypersensitivityreactions to SPIRIVA HandiHaler. In addition, SPIRIVA HandiHaler should beused with caution in patients with severe hypersensitivity to milk proteins.. 5.3 Paradoxical Bronchospasm. Inhaledmedicines, including SPIRIVA HandiHaler, may cause paradoxical bronchospasm. Ifthis occurs, treatment with SPIRIVA HandiHaler should be stopped and othertreatments considered.. 5.4 Worsening of Narrow-Angle Glaucoma. SPIRIVA HandiHaler should be used with caution inpatients with narrow-angle glaucoma. Prescribers and patients should be alertfor signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain ordiscomfort, blurred vision, visual halos or colored images in association withred eyes from conjunctival congestion and corneal edema). Instruct patients toconsult physician immediately should any of these signs or symptoms develop.. 5.5 Worsening of Urinary Retention. SPIRIVA HandiHaler should be used with caution inpatients with urinary retention. Prescribers and patients should be alert forsigns and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g.,difficulty passing urine, painful urination). Instruct patients to consult physicianimmediately should any of these signs or symptoms develop.. 5.6 Renal Impairment. Asa predominantly renally excreted drug, patients with moderate to severe renalimpairment (creatinine clearance of <=50 mL/min) treatedwith SPIRIVA HandiHaler should be monitored closely for anticholinergic sideeffects [see Clinical Pharmacology (12.3) ].