These highlights do not include all the information needed to use SPIRIVA HandiHaler safely and effectively. See full prescribing information for SPIRIVA HandiHaler. SPIRIVA HandiHaler (tiotropium bromide inhalation powder)Capsules for Respirato

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.

DO NOT SWALLOW SPIRIVA CAPSULESFOR USE WITH HANDIHALER DEVICE ONLY

FOR ORAL INHALATION ONLY

SPIRIVAcapsules 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, a 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) ].

SPIRIVAHandiHaler consists of SPIRIVA capsules and a 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 a HandiHaler device.

SPIRIVA HandiHaleris contraindicated in patients with a 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.

SPIRIVAHandiHaler is intended as a once-daily maintenance treatment for COPD and isnot indicated for the initial treatment of acute episodes of bronchospasm (i.e.,rescue therapy).

Immediate hypersensitivity reactions, includingangioedema (including swelling of the lips, tongue, or throat), itching, orrash may occur after administration of SPIRIVA HandiHaler. If such a 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 a 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.

Inhaledmedicines, including SPIRIVA HandiHaler, may cause paradoxical bronchospasm. Ifthis occurs, treatment with SPIRIVA HandiHaler should be stopped and othertreatments considered.

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 a physician immediately should any of these signs or symptoms develop.

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 a physicianimmediately should any of these signs or symptoms develop.

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) ].

The following adversereactions are described, or described in greater detail, in other sections:

Because clinical trialsare conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a 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 Trials

Thedata 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 a day.  The population had an age ranging from 39 to 87 years with 65% to85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forcedexpiratory volume in one second (FEV) 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 a Veteran'sAffairs 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 eva luatedSPIRIVA HandiHaler in patients with COPD. Table 1 shows all adverse reactionsthat occurred with a 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 1    Adverse Reactions(% Patients) in One-Year COPD Clinical Trials

Arthritis,coughing, and influenza-like symptoms occurred at a 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 a frequency of 1% to 3% in theplacebo-controlled trials where the rates exceeded that in the placebo groupinclude: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS),gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract.  In addition, among the adverse 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 eva luated SPIRIVA HandiHaler in patients with COPD. Theadverse reactions and the incidence rates were similar to those seen in the1-year controlled trials.

4-Year Trial The data described below reflect exposure to SPIRIVAHandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial.  In thistrial, 2986 patients were treated with SPIRIVA HandiHaler at the recommendeddose of 18 mcg once a day. The population had an age range from 40 to 88years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilatorFEV 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 Reactions Other 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.

Adversereactions have been identified during worldwide post-approval use of SPIRIVAHandiHaler. Because these reactions are reported voluntarily from a populationof uncertain size, it is not always possible to reliably estimate theirfrequency or establish a 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.

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.

Theco-administration of SPIRIVA HandiHaler with other anticholinergic-containingdrugs (e.g., ipratropium) has not been studied and is therefore notrecommended.

Noclinically significant interaction occurred between tiotropium and cimetidineor ranitidine [ see Clinical Pharmacology (12.3) ].

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 6 times therecommended human daily inhalation dose (RHDID) on a mg/m 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 a mg/m basis. In rabbits, tiotropium caused anincrease in post-implantation loss at an inhalation dose of approximately 360times the RHDID on a mg/m basis. Such effects were not observed atinhalation doses of approximately 4 and 80 times the RHDID on a mg/mbasis, respectively. These dose multiples may be over-estimated due todifficulties in measuring deposited doses in animal inhalation studies.

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

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 a nursing woman.

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.

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). A 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) ].

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) ].

Theeffects of hepatic impairment on the pharmacokinetics of tiotropium were notstudied.

Highdoses of tiotropium may lead to anticholinergic signs and symptoms. However,there were no systemic anticholinergic adverse effects following a singleinhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of12 healthy volunteers, bilateral conjunctivitis and dry mouth were seenfollowing repeated once-daily inhalation of 141 mcg of tiotropium.

Accidental Ingestion Acute intoxicationby inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is notwell-absorbed systemically.

Acase of overdose has been reported from postmarketing experience. A femalepatient was reported to have inhaled 30 capsules over a 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 a mg/mbasis, respectively. These dose multiples may be over-estimated due todifficulties in measuring deposited doses in animal inhalation studies.

SPIRIVAHandiHaler consists of a capsule dosage form containing a 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 (1α,2ß, 4ß, 5α,7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonanebromide monohydrate. It is a synthetic, non-chiral, quaternary ammoniumcompound. Tiotropium bromide is a white or yellowish white powder. It issparingly soluble in water and soluble in methanol.

Thestructural formula is:

Tiotropiumbromide (monohydrate) has a molecular mass of 490.4 and a molecular formula ofCHNOSBr • HO.

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 a mean of 10.4 mcgtiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total).In a study of 26 adult patients with COPD and severely compromised lungfunction [mean FEV 1.02 L (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.

Tiotropiumis a long-acting, antimuscarinic agent, which is often referred to as ananticholinergic. It has similar affinity to the subtypes of muscarinicreceptors, M to M.  In the airways, it exhibitspharmacological effects through inhibition of M-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 vivo studies, prevention of methacholine-induced bronchoconstriction effects wasdose-dependent and lasted longer than 24 hours. The bronchodilation followinginhalation of tiotropium is predominantly a site-specific effect.

CardiovascularEffects In a 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 (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 eva luated in a 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 a new onset of QTc >500 msecor QTc changes from baseline of ≥60 msec.

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 a lesser extent, in the lung, the intended organ. Many of thepharmacokinetic data described below were obtained with higher doses thanrecommended for therapy.

Absorption Following 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 tiotropium's bioavailability has not been studied.  Oralsolutions of tiotropium have an absolute bioavailability of 2% to 3%.Maximum tiotropium plasma concentrations were observed 5 minutes afterinhalation.

Distribution Tiotropium shows a 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 5 minutes after dry powder inhalation of an 18 mcg dose anddecreased in a multi-compartmental manner. Steady-state trough plasmaconcentrations were 3 to 4 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.

Metabolism The extent of metabolism appears to be small. This is evident from a 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 a 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 a 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 a 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.

Elimination The terminal elimination half-life of tiotropium was between 5 and 6 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 2 to 3 weekswith no accumulation thereafter.

Drug Interactions An 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 a 20% increase in the AUC, a 28% decrease in therenal clearance of tiotropium and no significant change in the Cand amount excreted in urine over 96 hours. Co-administration of tiotropiumwith ranitidine did not affect the pharmacokinetics of tiotropium.

SpecificPopulations GeriatricPatients As expected for drugs predominantly excreted renally, advanced age was associatedwith a 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 AUC 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) ].

RenalImpairment Since 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 AUCafterintravenous 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 AUC), 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) ].

HepaticImpairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were notstudied.

Noevidence of tumorigenicity was observed in a 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 a 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/m 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 a mg/mbasis). No sucheffects were observed at 0.009 mg/kg/day (approximately 4 times than theRHDID on a mg/m basis). The fertility index, however, was notaffected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times theRHDID on a mg/m basis). These dose multiples may be over-estimateddue to difficulties in measuring deposited doses in animal inhalation studies.

ReproductiveToxicology Studies No 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 6 times the RHDID on a mg/m basis, respectively. However, in rats, fetalresorption, litter loss, decreases in the number of live pups at birth and themean pup weights, and a delay in pup sexual maturation were observed atinhalation tiotropium doses of ≥0.078 mg/kg (approximately 35 times theRHDID on a mg/m 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 a mg/m 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 4 and 80 times the RHDID on a mg/m basis, respectively. These dose multiples may beover-estimated due to difficulties in measuring deposited doses in animalinhalation studies.

TheSPIRIVA HandiHaler (tiotropium bromide inhalation powder) clinical developmentprogram consisted of six Phase 3 studies in 2663 patients with COPD (1308receiving SPIRIVA HandiHaler): two 1-year, placebo‑controlled studies,two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlledstudies. These studies enrolled patients who had a clinical diagnosis of COPD,were 40 years of age or older, had a history of smoking greater than 10pack-years, had a forced expiratory volume in one second (FEV) lessthan or equal to 60% or 65% of predicted, and a ratio of FEV/FVC ofless than or equal to 0.7.

In these studies, SPIRIVA HandiHaler, administered once-daily in the morning,provided improvement in lung function (FEV), with peak effectoccurring within 3 hours following the first dose.

Two additional trialseva luated exacerbations: a 6-month, randomized, double-blind,placebo-controlled, multicenter clinical trial of 1829 COPD patients in a USVeterans 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 eva luated inthe 4-year multicenter trial.

6-Month to 1-YearEffects on Lung Function In the 1-year, placebo-controlled trials, the mean improvement in FEVat30 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 improvementsin FEV and forced vital capacity (FVC) were observed withpharmacodynamic steady state reached by Day 8 with once-daily treatment. Themean peak improvement in FEV, relative to baseline, was 0.28 to0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvementof lung function was maintained for 24 hours after a single dose andconsistently maintained over the 1-year treatment period with no evidence oftolerance.

In the two 6-month, placebo-controlled trials, serial spirometric eva luations wereperformed throughout daytime hours in Trial A (12 hours) and limited to 3 hoursin Trial B. The serial FEV values over 12 hours (Trial A)are displayed in Figure 1. These trials further support the improvement inpulmonary function (FEV) with SPIRIVA HandiHaler, which persistedover the spirometric observational period. Effectiveness was maintained for 24hours after administration over the 6-month treatment period.

Figure 1 Mean FEV Over Time (prior toand after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*

*Meansadjusted for center, treatment, and baseline effect. On Day 169, a total of 183and 149 patients in the SPIRIVA HandiHaler and placebo groups, respectively,completed the trial. The data for the remaining patients were imputed using thelast observation or least favorable observation carried forward.

Resultsof each of the 1-year ipratropium-controlled trials were similar to the resultsof the 1-year placebo-controlled trials. The results of one of these trials areshown in Figure 2.

Figure 2  Mean FEV Over Time(0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the TwoIpratropium-Controlled Studies*

*Meansadjusted for center, treatment, and baseline effect. On Day 92 (primaryendpoint), a total of 151 and 69 patients in the SPIRIVA HandiHaler andipratropium groups, respectively, completed through 3 months of observation.The data for the remaining patients were imputed using the last observation orleast favorable observation carried forward.

A randomized, placebo-controlled clinical study in 105 patients with COPDdemonstrated that bronchodilation was maintained throughout the 24-hour dosinginterval in comparison to placebo, regardless of whether SPIRIVA HandiHaler wasadministered in the morning or in the evening.

Throughout each week of the one-year treatment period in the two placebo-controlledtrials, patients taking SPIRIVA HandiHaler had a reduced requirement for theuse of rescue short-acting beta-agonists. Reduction in the use ofrescue short-acting beta-agonists, as compared to placebo, wasdemonstrated in one of the two 6-month studies.

4-Year Effects onLung Function A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992COPD patients was conducted to eva luate the long-term effects of SPIRIVAHandiHaler on disease progression (rate of decline in FEV).Patients were permitted to use all respiratory medications (includingshort-acting and long-acting beta-agonists, inhaled and systemic steroids, andtheophyllines) other than inhaled anticholinergics. The patients were 40 to 88years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilatorFEV of 39% predicted (range = 9% to 76%) at study entry.  There wasno difference between the groups in either of the co-primary efficacyendpoints, yearly rate of decline in pre- and post-bronchodilator FEV,as demonstrated by similar slopes of FEV decline over time (Figure3).

SPIRIVA HandiHalermaintained improvements in trough (pre-dose) FEV (adjusted meansover time: 87 to 103 mL) throughout the 4 years of the study (Figure 3).

Figure 3 Trough (pre-dose) FEV Mean Values at Each Time Point

Repeated measureANOVA was used to estimate means. Means are adjusted for baseline measurements.Baseline trough FEV (observed mean) = 1.12. Patients with ≥3acceptable pulmonary function tests after Day 30 and non-missing baseline valuewere included in the analysis.

Exacerbations The effect of SPIRIVA HandiHaler on COPD exacerbations was eva luated in twoclinical trials: a 4-year clinical trial described above and a 6-month clinicaltrial of 1829 COPD patients in a Veterans Affairs setting. In the 6-monthtrial, 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 daysrequiring treatment with antibiotics, systemic steroids, or hospitalization.  Thepopulation had an age ranging from 40 to 90 years with 99% males, 91%Caucasian, and had COPD with a mean pre-bronchodilator FEV percentpredicted of 36% (range = 8% to 93%).  Patients were permitted to userespiratory medications (including short-acting and long-acting beta-agonists,inhaled and systemic steroids, and theophyllines) other than inhaledanticholinergics. In the 6-month trial, the co-primary endpoints were theproportion of patients with COPD exacerbation and the proportion of patientswith hospitalization due to COPD exacerbation.  SPIRIVA HandiHalersignificantly reduced the proportion of COPD patients who experiencedexacerbations 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 proportionof patients with hospitalization due to COPD exacerbations in patients who usedSPIRIVA HandiHaler compared to placebo was 7.0% vs 9.5%, respectively; OR =0.72; 95% CI = 0.51, 1.01; p = 0.056.

Exacerbations wereeva luated as a secondary outcome in the 4-year multicenter trial. In thistrial, COPD exacerbations were defined as an increase or new onset of more thanone of the following respiratory symptoms (cough, sputum, sputum purulence,wheezing, dyspnea) with a duration of three or more days requiring treatmentwith antibiotics and/or systemic (oral, intramuscular, or intravenous)steroids.  SPIRIVA HandiHaler significantly reduced the risk of an exacerbationby 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reducedthe risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI =0.78, 0.95; p<0.002) compared to placebo.  The median time to firstexacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebogroup to 16.7 months (95% CI = 14.9, 17.9) in the SPIRIVA HandiHaler group.

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 a 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:

Storage Storeat 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [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.

See FDA-approved Patient Labeling (17.6)

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.

Patientsshould be informed that SPIRIVA HandiHaler can produce paradoxicalbronchospasm. If paradoxical bronchospasm occurs, patients should discontinueSPIRIVA HandiHaler.

Difficultypassing urine and dysuria may be symptoms of new or worsening prostatichyperplasia or bladder outlet obstruction. Patients should be instructed toconsult a physician immediately should any of these signs or symptoms develop.

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.

Patientsshould understand that SPIRIVA HandiHaler is a once-daily maintenancebronchodilator and should not be used for immediate relief of breathingproblems (i.e., as a rescue medication).

PatientInformation and Patient’s 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 USA

Marketed by:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAandPfizer IncNew York, NY 10017 USA

Licensed from:Boehringer Ingelheim International GmbH

Address medical inquiries to: (800)542-6257 or (800) 459-9906 TTY.

SPIRIVA® and HandiHaler® are registered trademarks and are used under license from Boehringer Ingelheim InternationalGmbH.

©Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

SPIRIVA® (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 inhalationdevice is covered by U.S. Design Patent No. D355,029 with other patentspending.

Rev:December 2009

IT1600WL160910004551/0765626-08

Relabeling of "Additional Barcode"  by:Physicians Total Care, Inc.Tulsa, OK    74146

Patient Information

SPIRIVA (speh REE vah) HandiHaler (tiotropium bromide inhalation powder)

Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the HandiHaler device. 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 HandiHaler? SPIRIVA HandiHaler is a 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). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.

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

SPIRIVA HandiHaler has not been studied in children.

Who should not take SPIRIVA HandiHaler?

Do not use SPIRIVA HandiHaler if you:

Allergic reactions may include itching, rash, or swelling of the lips, tongue, or throat (trouble swallowing).

What should I tell my doctor before using SPIRIVA HandiHaler?

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

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

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

How should I take SPIRIVA HandiHaler?

What should I avoid while using SPIRIVA HandiHaler?

Do not let the powder from the SPIRIVA capsule get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.

What are the possible side effects of SPIRIVA HandiHaler?

SPIRIVA 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.

Other side effects with SPIRIVA HandiHaler include:

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

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

How do I store SPIRIVA HandiHaler?

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

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

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

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

For 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 HandiHaler?

Active ingredient: tiotropiumInactive ingredient: lactose monohydrate

What is COPD (Chronic Obstructive Pulmonary Disease)?

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

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 GmbH

SPIRIVA and HandiHaler are registered trademarks and are used under license from Boehringer Ingelheim International GmbH.

©Copyright 2009 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

Rev: December 2009

IT1600WL160910004551/0765626-08

Patient's Instructions for Use

SPIRIVA HandiHaler (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 Patient's 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 a 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.

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011