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.

2  DOSAGE AND ADMINISTRATION

DO NOT SWALLOW SPIRIVA CAPSULES
FOR 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)].

3  DOSAGE FORMS AND STRENGTHS

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.

4  CONTRAINDICATIONS

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.

5  WARNINGS AND PRECAUTIONS

5.1  Not for Acute Use

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).

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 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.

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 a 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 a 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)].

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)]

6.1  Clinical Trials Experience

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, 1308patientswere treated with SPIRIVA HandiHaler at the recommended dose of 18mcgonce 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 (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 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 18mcg 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-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 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.

6.2  Postmarketing Experience

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.

7  DRUG INTERACTIONS

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)].

8  USE IN SPECIFIC POPULATIONS

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 6 times therecommended human daily inhalation dose (RHDID) on a mg/m2 basis,respectively. However, in rats, tiotropium caused fetal resorption, litter loss,decreases in the number of live pups at birth and the mean pup weights, and adelay in pup sexual maturation at inhalation tiotropium doses of approximately35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused anincrease in post-implantation loss at an inhalation dose of approximately 360times the RHDID on a mg/m2 basis. Such effects were not observed atinhalation doses of approximately 4 and 80 times the RHDID on a 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 a 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, 426were <65years, 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)].

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.

10  OVERDOSAGE

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 se