Tiova

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Tiova uses

•   indications and usage
•   dosage and administration
•   dosage forms and strengths
•   contraindications
•   warnings and precautions
•   adverse reactions
•   drug interactions
•   use in specific populations
•   overdosage
•   description
•   clinical pharmacology
•   nonclinical toxicology
•   clinical studies
•   how supplied/storageand handling
•   patient counseling information
• Tiova reviews

1  INDICATIONS AND USAGE

Tiova HANDIHALER (tiotropium bromide inhalationpowder) is indicated for the long-term, once-daily, maintenance treatmentof bronchospasm associated with chronic obstructive pulmonary disease(COPD), including chronic bronchitis and emphysema. Tiova HANDIHALERis indicated to reduce exacerbations in COPD patients.

Tiova HANDIHALER is an anticholinergic indicatedfor the long-term, once-daily, maintenance treatment of bronchospasmassociated with chronic obstructive pulmonary disease (COPD), andfor reducing COPD exacerbations (1)

2  DOSAGE AND ADMINISTRATION

For oral inhalation only. Do not swallow SPIRIVAcapsules, as the intended effects on the lungs will not be obtained. The contents of the Tiova capsules should only be used with theHANDIHALER device [see Overdosage (10) ].

The recommended dose of Tiova HANDIHALER is two inhalationsof the powder contents of one Tiova capsule, once-daily, with theHANDIHALER device [see Patient Counseling Information (17) ]. Do not take morethan one dose in 24 hours.

Foradministration of Tiova HANDIHALER, a Tiova capsule is placedinto the center chamber of the HANDIHALER device. The Tiova capsuleis pierced by pressing and releasing the green piercing button onthe side of the HANDIHALER device. The Tiova formulation is dispersedinto the air stream when the patient inhales through the mouthpiece [see Patient Counseling Information (17) ].

No dosage adjustment is required for geriatric, hepatically-impaired,or renally-impaired patients. However, patients with moderate to severerenal impairment given Tiova HANDIHALER should be monitored closelyfor anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3) ].

• For oral inhalation only. DO NOT swallow Tiova capsules. Only use Tiova capsules with the HANDIHALER device (2)
• Two inhalations of the powder contents of a single SPIRIVAcapsule (18 mcg) once daily (2)

3  DOSAGE FORMS AND STRENGTHS

Inhalation Powder: Tiova HANDIHALER consistsof Tiova capsules containing Tiova powder for oral inhalationand a HANDIHALER device. Tiova capsules contain 18 mcg of tiotropiumin a light green, hard gelatin capsule with TI 01 printed on one sideand Boehringer Ingelheim company logo on the other side. The HANDIHALERdevice is only intended for use with the Tiova capsules.

Inhalation powder: Tiova capsules contain18 mcg Tiova powder for use with HANDIHALER device (3)

4  CONTRAINDICATIONS

Tiova HANDIHALER is contraindicated in patients with a hypersensitivityto Tiova, ipratropium, or any components of this product . In clinical trials and postmarketing experience withSPIRIVA HANDIHALER, immediate hypersensitivity reactions, includingangioedema (including swelling of the lips, tongue, or throat), itching,or rash have been reported .

Hypersensitivity to Tiova,ipratropium or any components of Tiova capsules (4)

5  WARNINGS AND PRECAUTIONS

• Not for acute use: Not a rescue medication
• Immediate hypersensitivity reactions: Discontinue SPIRIVAHANDIHALER at once and consider alternatives if immediate hypersensitivityreactions, including angioedema, bronchospasm, or anaphylaxis, occur. Use with caution in patients with severe hypersensitivity to milkproteins. (5.2)
• Paradoxical bronchospasm: Discontinue Tiova HANDIHALERand consider other treatments if paradoxical bronchospasm occurs (5.3)
• Worsening of narrow-angle glaucoma may occur. Use withcaution in patients with narrow-angle glaucoma and instruct patientsto consult a physician immediately if this occurs. (5.4)
• Worsening of urinary retention may occur. Use with cautionin patients with prostatic hyperplasia or bladder-neck obstructionand instruct patients to consult a physician immediately if this occurs. (5.5)

5.1  Not for Acute Use

Tiova HANDIHALER is intended as a once-dailymaintenance treatment for COPD and should not be used for relief ofacute symptoms, i.e., as rescue therapy for the treatment of acuteepisodes of bronchospasm.

5.2  Immediate HypersensitivityReactions

Immediate hypersensitivityreactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, oritching, may occur after administration of Tiova HANDIHALER. Ifsuch a reaction occurs, therapy with Tiova HANDIHALER should bestopped at once and alternative treatments should be considered. Giventhe similar structural formula of atropine to Tiova, patientswith a history of hypersensitivity reactions to atropine or its derivativesshould be closely monitored for similar hypersensitivity reactionsto Tiova HANDIHALER. In addition, Tiova HANDIHALER should be usedwith caution in patients with severe hypersensitivity to milk proteins.

5.3  Paradoxical Bronchospasm

Inhaled medicines, including Tiova HANDIHALER,may cause paradoxical bronchospasm. If this occurs, it should be treatedimmediately with an inhaled short-acting beta₂-agonist such as albuterol. Treatment with Tiova HANDIHALER shouldbe stopped and other treatments considered.

5.4  Worsening of Narrow-AngleGlaucoma

Tiova HANDIHALERshould be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms ofacute narrow-angle glaucoma. Instruct patientsto consult a physician immediately should any of these signs or symptomsdevelop.

5.5  Worsening of UrinaryRetention

Tiova HANDIHALERshould be used with caution in patients with urinary retention. Prescribersand patients should be alert for signs and symptoms of urinary retention(e.g., difficulty passing urine, painful urination), especially inpatients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any ofthese signs or symptoms develop.

5.6  Renal Impairment

As a predominantly renally excreted drug,patients with moderate to severe renal impairment (creatinine clearanceof <60 mL/min) treated with Tiova HANDIHALER should be monitoredclosely for anticholinergic side effects [see ClinicalPharmacology (12.3) ].

6  ADVERSE REACTIONS

The following adverse reactions are described, or described in greaterdetail, in other sections:

• Immediate hypersensitivity reactions [see Warnings and Precautions ]
• Paradoxical bronchospasm [see Warningsand Precautions (5.3) ]
• Worsening of narrow-angle glaucoma [seeWarnings and Precautions (5.4) ]
• Worsening of urinary retention [see Warningsand Precautions (5.5) ]

The most common adverse reactions(>5% incidence in the 1-year placebo-controlled trials) were upperrespiratory tract infection, dry mouth, sinusitis, pharyngitis, non-specificchest pain, urinary tract infection, dyspepsia, and rhinitis (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800)542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1  Clinical Trials Experience

Because clinical trials are conducted under widely varyingconditions, the incidence of adverse reactions observed in the clinicaltrials of a drug cannot be directly compared to the incidences inthe clinical trials of another drug and may not reflect the incidencesobserved in practice.

6-Month to 1-Year Trials

The data described below reflect exposureto Tiova HANDIHALER in 2663 patients. SPIRIVA HANDIHALER was studiedin two 1-year placebo-controlled trials, two 1-year active-controlledtrials, and two 6-month placebo-controlled trials in patients withCOPD. In these trials, 1308 patients were treated with Tiova HANDIHALERat the recommended dose of 18 mcg once a day. The population hadan age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian,and had COPD with a mean pre-bronchodilator forced expiratory volumein one second (FEV₁) percent predicted of 39%to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatichypertrophy or bladder outlet obstruction were excluded from thesetrials. An additional 6-month trial conducted in a Veteran’s Affairssetting is not included in this safety database because only seriousadverse events were collected.

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

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

Table 1 Adverse Reactions(% Patients) in One-Year COPD Clinical Trials

Body System (Event)	Placebo-Controlled Trials		Ipratropium-Controlled Trials
	Tiova (n = 550)	Placebo (n = 371)	Tiova (n = 356)	Ipratropium (n = 179)
Body as a Whole Chest Pain (non-specific)	7	5	5	2
Edema, Dependent	5	4	3	5
Gastrointestinal SystemDisorders Dry Mouth	16	3	12	6
Dyspepsia	6	5	1	1
Abdominal Pain	5	3	6	6
Constipation	4	2	1	1
Vomiting	4	2	1	2
Musculoskeletal System Myalgia	4	3	4	3
Resistance Mechanism Disorders Infection	4	3	1	3
Moniliasis	4	2	3	2
Respiratory System (Upper) Upper Respiratory Tract Infection	41	37	43	35
Sinusitis	11	9	3	2
Pharyngitis	9	7	7	3
Rhinitis	6	5	3	2
Epistaxis	4	2	1	1
Skin and Appendage Disorders Rash	4	2	2	2
Urinary System Urinary Tract Infection	7	5	4	2

Arthritis, coughing, and influenza-likesymptoms occurred at a rate of ≥3% in the Tiova HANDIHALER treatmentgroup, but were <1% in excess of the placebo group.

Other reactions that occurred in the SPIRIVAHANDIHALER group at a frequency of 1% to 3% in the placebo-controlledtrials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction,leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; GastrointestinalSystem Disorders: gastrointestinal disorder nototherwise specified (NOS), gastroesophageal reflux, stomatitis (includingulcerative stomatitis); Metabolic and NutritionalDisorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletalpain; Cardiac Events: anginapectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition,among the adverse reactions observed in the clinical trials with anincidence of <1% were atrial fibrillation, supraventricular tachycardia,angioedema, and urinary retention.

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

Two multicenter,6-month, controlled studies evaluated Tiova HANDIHALER in patientswith COPD. The adverse reactions and the incidence rates were similarto those seen in the 1-year controlled trials.

4-Year Trial

The data described below reflect exposure to Tiova HANDIHALERin 5992 COPD patients in a 4-year placebo-controlled trial. In thistrial, 2986 patients were treated with Tiova HANDIHALER at the recommendeddose of 18 mcg once a day. The population had an age range from 40to 88 years, was 75% male, 90% Caucasian, and had COPD with a meanpre-bronchodilator FEV₁ percent predicted of40%. Patients with narrow-angle glaucoma, or symptomatic prostatichypertrophy or bladder outlet obstruction were excluded from thesetrials. When the adverse reactions were analyzed with a frequencyof ≥3% in the Tiova HANDIHALER group where the rates in the SPIRIVAHANDIHALER 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%), drymouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%),and arthralgia (4.2%, 3.1%).

Additional Adverse Reactions

Other adverse reactions not previously listed that were reportedmore frequently in COPD patients treated with Tiova HANDIHALER thanplacebo include: dehydration, skin ulcer, stomatitis, gingivitis,oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.

6.2  Postmarketing Experience

Adverse reactions have been identified during worldwidepost-approval use of Tiova HANDIHALER. Because these reactions arereported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establisha causal relationship to drug exposure. These adverse reactions are:application site irritation (glossitis, mouth ulceration, and pharyngolaryngealpain), dizziness, dysphagia, hoarseness, intestinal obstruction includingileus paralytic, intraocular pressure increased, oral candidiasis,palpitations, pruritus, tachycardia, throat irritation, and urticaria.

7  DRUG INTERACTIONS

Anticholinergics: May interact additivelywith concomitantly used anticholinergic medications. Avoid administrationof Tiova HANDIHALER with other anticholinergic-containing drugs.

7.1  Sympathomimetics,Methylxanthines, Steroids

Tiova HANDIHALER has been used concomitantly with short-actingand long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines,and oral and inhaled steroids without increases in adverse reactions.

7.2  Anticholinergics

There is potential for an additive interactionwith concomitantly used anticholinergic medications. Therefore, avoidcoadministration of Tiova HANDIHALER with other anticholinergic-containingdrugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6) ].

8  USE IN SPECIFIC POPULATIONS

Patients with moderate to severe renal impairmentshould be monitored closely for potential anticholinergic side effects

8.1  Pregnancy

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. SPIRIVA HANDIHALER should be used during pregnancy only if the potentialbenefit justifies the potential risk to the fetus.

No evidence of structural alterations was observed inrats and rabbits at approximately 790 and 8 times the maximum recommendedhuman daily inhalation dose (MRHDID), respectively (on a mcg/m² basis at maternal inhalation doses of 1471 and 7mcg/kg/day in rats and rabbits, respectively). However, in rats, tiotropiumcaused fetal resorption, litter loss, decreases in the number of livepups at birth and the mean pup weights, and a delay in pup sexualmaturation at inhalation Tiova doses of approximately 40 timesthe MRHDID (on a mcg/m² basis at a maternalinhalation dose of 78 mcg/kg/day). In rabbits, Tiova caused anincrease in post-implantation loss at an inhalation dose of approximately430 times the MRHDID (on a mcg/m² basisat a maternal inhalation dose of 400 mcg/kg/day). Such effects werenot observed at inhalation doses of approximately 5 and 95 times theMRHDID, respectively (on a mcg/m² basisat inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

8.2  Labor and Delivery

The safety and effectiveness of Tiova HANDIHALER has not been studiedduring labor and delivery.

8.3  Nursing Mothers

Clinical data from nursing women exposed to Tiova are not available. Based on lactating rodent studies, Tiova is excreted into breastmilk. It is not known whether Tiova is excreted in human milk,but because many drugs are excreted in human milk and given thesefindings in rats, caution should be exercised if Tiova HANDIHALERis administered to a nursing woman.

8.4  Pediatric Use

SPIRIVAHANDIHALER is not indicated for use in children. The safety and effectivenessof Tiova HANDIHALER in pediatric patients have not been established.

8.5  Geriatric Use

Based on available data, no adjustment ofSPIRIVA HANDIHALER dosage in geriatric patients is warranted .

Of the total numberof patients who received Tiova HANDIHALER in the 1-year clinicaltrials, 426 were <65 years, 375 were 65 to 74 years, and 105 were≥75 years of age. Within each age subgroup, there were no differencesbetween the proportion of patients with adverse events in the SPIRIVAHANDIHALER and the comparator groups for most events. Dry mouth increasedwith age in the Tiova HANDIHALER group (differences from placebowere 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups).A higher frequency of constipation and urinary tract infections withincreasing age was observed in the Tiova HANDIHALER group in theplacebo-controlled studies. The differences from placebo for constipationwere 0%, 1.8%, and 7.8% for each of the age groups. The differencesfrom placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%.No overall differences in effectiveness were observed among thesegroups.

8.6  Renal Impairment

Patients with moderate to severe renal impairment(creatinine clearance of <60 mL/min) treated with Tiova HANDIHALERshould be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6),and Clinical Pharmacology (12.3) ].

8.7  Hepatic Impairment

The effects of hepatic impairment on thepharmacokinetics of Tiova were not studied.

10  OVERDOSAGE

Highdoses of Tiova may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects followinga single inhaled dose of up to 282 mcg Tiova in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis anddry mouth were seen following repeated once-daily inhalation of 141mcg of Tiova.

Treatment of overdosage consists of discontinuation of Tiova HANDIHALERtogether with institution of appropriate symptomatic and/or supportivetherapy.

AccidentalIngestion

Acute intoxicationby inadvertent oral ingestion of Tiova capsules is unlikely sinceit is not well-absorbed systemically.

A case of overdose has been reported frompostmarketing experience. A female patient was reported to have inhaled30 capsules over a 2.5 day period, and developed altered mental status,tremors, abdominal pain, and severe constipation. The patient washospitalized, Tiova HANDIHALER was discontinued, and the constipationwas treated with an enema. The patient recovered and was dischargedon the same day.

11  DESCRIPTION

Tiova HANDIHALER consists of Tiova capsulesand a HANDIHALER device. Each light green, hard gelatin Tiova capsulecontains a dry powder consisting of 18 mcg Tiova (equivalentto 22.5 mcg Tiova bromide monohydrate) blended with lactose monohydrate(which may contain milk proteins).

The contents of Tiova capsules are intended for oral inhalationonly, and are intended for administration only with the HANDIHALERdevice.

The active component ofSPIRIVA HANDIHALER is Tiova. The drug substance, Tiova bromidemonohydrate, is an anticholinergic with specificity for muscarinicreceptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^2,4]nonane bromide monohydrate. It is a synthetic,non-chiral, quaternary ammonium compound. Tiova bromide is awhite or yellowish white powder. It is sparingly soluble in waterand soluble in methanol.

The structuralformula is:

Tiotropiumbromide (monohydrate) has a molecular mass of 490.4 and a molecularformula of C₁₉H₂₂NO₄S₂Br - H₂O.

The HANDIHALER device is aninhalation device used to inhale the dry powder contained in the SPIRIVAcapsule. The dry powder is delivered from the HANDIHALER device atflow rates as low as 20 L/min. Under standardized in vitro testing, the HANDIHALER device deliversa mean of 10.4 mcg Tiova when tested at a flow rate of 39 L/minfor 3.1 seconds (2 L total). In a study of 26 adult patients withCOPD and severely compromised lung function [mean FEV₁ 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to65%)], the median peak inspiratory flow (PIF) through the HANDIHALERdevice was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drugdelivered to the lungs will vary depending on patient factors suchas inspiratory flow and peak inspiratory flow through the HANDIHALERdevice, which may vary from patient to patient, and may vary withthe exposure time of the Tiova capsule outside the blister pack.

Tiova Structure

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

Tiova is a long-acting, antimuscarinic agent, which is oftenreferred to as an anticholinergic. It has similar affinity to thesubtypes of muscarinic receptors, M₁ to M₅. In the airways, it exhibits pharmacological effectsthrough inhibition of M₃-receptors at the smoothmuscle leading to bronchodilation. The competitive and reversiblenature of antagonism was shown with human and animal origin receptorsand isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstrictioneffects was dose-dependent and lasted longer than 24 hours. The bronchodilationfollowing inhalation of Tiova is predominantly a site-specificeffect.

12.2  Pharmacodynamics

Cardiac Electrophysiology

In amulticenter, randomized, double-blind trial using Tiova dry powderfor inhalation that enrolled 198 patients with COPD, the number ofsubjects with changes from baseline-corrected QT interval of 30 to60 msec was higher in the Tiova HANDIHALER group as compared withplacebo. This difference was apparent using both the Bazett [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 had either QTcB or QTcF of >500 msec. Other clinical studies with Tiova HANDIHALER did not detect an effectof the drug on QTc intervals.

The effect of Tiova dry powder for inhalation on QT intervalwas also evaluated in a randomized, placebo- and positive-controlledcrossover study in 53 healthy volunteers. Subjects received tiotropiumdry powder for inhalation 18 mcg, 54 mcg (3 times the recommendeddose), or placebo for 12 days. ECG assessments were performed at baselineand throughout the dosing interval following the first and last doseof study medication. Relative to placebo, the maximum mean changefrom baseline in study-specific QTc interval was 3.2 msec and 0.8msec for Tiova dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes frombaseline of ≥60 msec.

12.3  Pharmacokinetics

Tiova is administered by dry powder inhalation. Some of thepharmacokinetic data described below were obtained with higher dosesthan recommended for therapy. A dedicated pharmacokinetic study inpatients with COPD evaluating once-daily Tiova delivered fromthe RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) fromthe HANDIHALER device resulted in a similar systemic exposure betweenthe two products.

Absorption

Following dry powderinhalation by young healthy volunteers, the absolute bioavailabilityof 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of Tiova have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of Tiova. Maximumtiotropium plasma concentrations were observed 7 minutes after inhalation.

Distribution

Tiova is 72% bound to plasma proteinand had a volume of distribution of 32 L/kg after intravenous administrationto young healthy volunteers. Local concentrations in the lung arenot known, but the mode of administration suggests substantially higherconcentrations in the lung. Studies in rats have shown that tiotropiumdoes not readily penetrate the blood-brain barrier.

Elimination

The terminal half-life of Tiova in COPD patients followingonce daily inhalation of 5 mcg Tiova was approximately 25 hours. Total clearance was 880 mL/min after intravenous administration inyoung healthy volunteers. After chronic once-daily dry powder inhalationby COPD patients, pharmacokinetic steady state was reached by day 7with no accumulation thereafter.

Metabolism

The extentof metabolism is small. This is evident from a urinary excretion of74% of unchanged substance after an intravenous dose to young healthyvolunteers. Tiova, an ester, is nonenzymatically cleaved to thealcohol N-methylscopine and dithienylglycolic acid, neither of whichbinds to muscarinic receptors.

In vitro experiments with humanliver microsomes and human hepatocytes suggest that a fraction ofthe administered dose (74% of an intravenous dose is excreted unchangedin the urine, leaving 25% for metabolism) is metabolized by cytochromeP450-dependent oxidation and subsequent glutathione conjugation toa variety of Phase II metabolites. This enzymatic pathway can be inhibitedby CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole,and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolicpathway that is responsible for the elimination of a small part ofthe administered dose. In vitro studies using human liver microsomes showed that Tiova in supra-therapeuticconcentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6,2E1, or 3A4.

Excretion

Intravenously administered Tiova bromide is mainlyexcreted unchanged in urine (74%). After dry powder inhalation toCOPD patients at steady state, urinary excretion was 7% (1.3 µg) ofthe unchanged dose over 24 hours. The renal clearance of tiotropiumexceeds the creatinine clearance, indicating secretion into the urine.

Specific Populations

Geriatric Patients

As expectedfor all predominantly renally excreted drugs, advancing age was associatedwith a decrease of Tiova renal clearance (365 mL/min in COPDpatients <65 years to 271 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC_0-6,ss and C_max,ss values following administrationvia HANDIHALER device.

Renal Impairment

Following 4-week SPIRIVAHANDIHALER or Tiova RESPIMAT once daily dosing in patients withCOPD, mild renal impairment (creatinine clearance 60-90 mL/min) resultedin 6-23% higher AUC_0-6,ss and 6-17% higherC_max,ss values; moderate renal impairment (creatinineclearance 30-60 mL/min) resulted in 54-57% higher AUC_0-6,ss and 15-31% higher C_max,ss values comparedto COPD patients with normal renal function (creatinine clearance>90 mL/min). There is insufficient data for Tiova exposure inpatients with severe renal impairment (creatinine clearance <30mL/min) following inhalation of Tiova HANDIHALER or Tiova RESPIMAT.However AUC_0-4 and C_max were 94% and 52% higher, respectively, in patients with severe renalimpairment following intravenous infusion of Tiova bromide.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokineticsof Tiova were not studied.

Drug Interactions

An interaction study with Tiova (14.4 mcg intravenous infusionover 15 minutes) and cimetidine 400 mg three times daily or ranitidine300 mg once daily was conducted. Concomitant administration of cimetidinewith Tiova resulted in a 20% increase in the AUC_0-4h, a 28% decrease in the renal clearance of Tiova and no significantchange in the C_max and amount excreted in urineover 96 hours. Co-administration of Tiova with ranitidine didnot affect the pharmacokinetics of Tiova.

Common concomitant medications (long-actingbeta₂-adrenergic agonists (LABA), inhaled corticosteroids(ICS)) used by patients with COPD were not found to alter the exposureto Tiova.

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was observedin a 104-week inhalation study in rats at Tiova doses up to 59mcg/kg/day, in an 83-week inhalation study in female mice at dosesup to 145 mcg/kg/day, and in a 101-week inhalation study in male miceat doses up to 2 mcg/kg/day. These doses correspond to approximately30, 40, and 0.5 times the recommended human daily inhalation dose(MRHDID) on a mcg/m² basis, respectively.

Tiova bromide demonstrated no evidenceof mutagenicity or clastogenicity in the following assays: the bacterialgene mutation assay, the V79 Chinese hamster cell mutagenesis assay,the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesisin primary rat hepatocytes in vitro assay.

In rats, decreases inthe number of corpora lutea and the percentage of implants were notedat inhalation Tiova doses of 78 mcg/kg/day or greater (approximately40 times the MRHDID on a mcg/m² basis).No such effects were observed at 9 mcg/kg/day (approximately 5 timesthe MRHDID on a mcg/m² basis). The fertilityindex, however, was not affected at inhalation doses up to 1689 mcg/kg/day(approximately 910 times the MRHDID on a mcg/m² basis).

14  CLINICAL STUDIES

The Tiova HANDIHALER (tiotropium bromide inhalation powder) clinicaldevelopment program consisted of six Phase 3 studies in 2663 patientswith COPD (1308 receiving Tiova HANDIHALER): two 1-year, placebo-controlledstudies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlledstudies. These studies enrolled patients who had a clinical diagnosisof COPD, were 40 years of age or older, had a history of smoking greaterthan 10 pack-years, had a forced expiratory volume in one second (FEV₁) less than or equal to 60% or 65% of predicted, anda ratio of FEV₁/FVC of less than or equal to0.7.

In these studies, SPIRIVAHANDIHALER, administered once-daily in the morning, provided improvementin lung function (FEV₁), with peak effect occurringwithin 3 hours following the first dose.

Two additional trials evaluated exacerbations: a 6-month,randomized, double-blind, placebo-controlled, multicenter clinicaltrial of 1829 COPD patients in a US Veterans Affairs setting and a4-year, randomized, double-blind, placebo-controlled, multicenter,clinical trial of 5992 COPD patients. Long-term effects on lung functionand other outcomes, were also evaluated in the 4-year multicentertrial.

6-Monthto 1-Year Effects on Lung Function

Inthe 1-year, placebo-controlled trials, the mean improvement in FEV₁ at 30 minutes was 0.13 liters (13%) with a peak improvementof 0.24 liters (24%) relative to baseline after the first dose (Day1). Further improvements in FEV₁ and forcedvital capacity (FVC) were observed with pharmacodynamic steady statereached by Day 8 with once-daily treatment. The mean peak improvementin FEV₁, relative to baseline, was 0.28 to0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a singledose and consistently maintained over the 1-year treatment periodwith no evidence of tolerance.

In the two 6-month, placebo-controlled trials, serial spirometricevaluations were performed throughout daytime hours in Trial A (12hours) and limited to 3 hours in Trial B. The serial FEV₁ values over 12 hours (Trial A) are displayed in Figure1. These trials further support the improvement in pulmonary function(FEV₁) with Tiova HANDIHALER, which persistedover the spirometric observational period. Effectiveness was maintainedfor 24 hours after administration over the 6-month treatment period.

Figure 1 Mean FEV₁ Over Time (prior to and after administration of studydrug) on Days 1 and 169 for Trial A (a Six-Month Placebo-ControlledStudy)*

*Means adjusted for center, treatment, and baseline effect. On Day169, a total of 183 and 149 patients in the Tiova HANDIHALER andplacebo groups, respectively, completed the trial. The data for theremaining patients were imputed using the last observation or leastfavorable observation carried forward.

Results of each of the 1-year ipratropium-controlledtrials were similar to the results of the 1-year placebo-controlledtrials. The results of one of these trials are shown in Figure 2.

Figure 2 MeanFEV₁ Over Time (0 to 6 hours post-dose) onDays 1 and 92, Respectively for One of the Two Ipratropium-ControlledStudies*

*Means adjusted for center, treatment, and baseline effect. On Day92 (primary endpoint), a total of 151 and 69 patients in the SPIRIVAHANDIHALER and ipratropium groups, respectively, completed through3 months of observation. The data for the remaining patients wereimputed using the last observation or least favorable observationcarried forward.

A randomized,placebo-controlled clinical study in 105 patients with COPD demonstratedthat bronchodilation was maintained throughout the 24-hour dosinginterval in comparison to placebo, regardless of whether Tiova HANDIHALERwas administered in the morning or in the evening.

Throughout each week of the 1-year treatment periodin the two placebo-controlled trials, patients taking Tiova HANDIHALERhad a reduced requirement for the use of rescue short-acting beta₂-agonists. Reduction in the use of rescue short-actingbeta₂-agonists, as compared to placebo, wasdemonstrated in one of the two 6-month studies.

4-Year Effects on Lung Function

A 4-year, randomized, double-blind, placebo-controlled,multicenter clinical trial involving 5992 COPD patients was conductedto evaluate the long-term effects of Tiova HANDIHALER on diseaseprogression (rate of decline in FEV₁). Patientswere permitted to use all respiratory medications (including short-actingand long-acting beta-agonists, inhaled and systemic steroids, andtheophyllines) other than inhaled anticholinergics. The patients were40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosisof COPD and a mean pre-bronchodilator FEV₁ of39% predicted (range = 9% to 76%) at study entry. There was no differencebetween the groups in either of the co-primary efficacy endpoints,yearly rate of decline in pre- and post-bronchodilator FEV₁, as demonstrated by similar slopes of FEV₁ decline over time (Figure 3).

Tiova HANDIHALER maintained improvements in trough(pre-dose) FEV₁ (adjusted means over time:87 to 103 mL) throughout the 4 years of the study (Figure 3).

Figure 3 Trough(pre-dose) FEV₁ Mean Values at Each Time Point

Repeated measure ANOVA was used to estimate means. Means are adjustedfor baseline measurements. Baseline trough FEV₁ (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary functiontests after Day 30 and non-missing baseline value were included inthe analysis.

Exacerbations

The effect of SPIRIVAHANDIHALER on COPD exacerbations was evaluated in two clinical trials:a 4-year clinical trial described above and a 6-month clinical trialof 1829 COPD patients in a Veterans Affairs setting. In the 6-monthtrial, COPD exacerbations were defined as a complex of respiratorysymptoms (increase or new onset) of more than one of the following:cough, sputum, wheezing, dyspnea, or chest tightness with a durationof at least 3 days requiring treatment with antibiotics, systemicsteroids, or hospitalization. The population had an age ranging from40 to 90 years with 99% males, 91% Caucasian, and had COPD with amean pre-bronchodilator FEV₁ percent predictedof 36% (range = 8% to 93%). Patients were permitted to use respiratorymedications (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 werethe proportion of patients with COPD exacerbation and the proportionof patients with hospitalization due to COPD exacerbation. SPIRIVAHANDIHALER significantly reduced the proportion of COPD patients whoexperienced exacerbations compared to placebo (27.9% vs 32.3%, respectively;Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99;p = 0.037). The proportion of patients with hospitalization due toCOPD exacerbations in patients who used Tiova HANDIHALER comparedto placebo was 7.0% vs 9.5%, respectively; OR = 0.72; 95% CI = 0.51,1.01; p = 0.056.

Exacerbationswere evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or newonset of more than one of the following respiratory symptoms (cough,sputum, sputum purulence, wheezing, dyspnea) with a duration of threeor more days requiring treatment with antibiotics and/or systemic(oral, intramuscular, or intravenous) steroids. Tiova HANDIHALERsignificantly reduced the risk of an exacerbation by 14% (Hazard Ratio(HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the riskof exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI= 0.78, 0.95; p<0.002) compared to placebo. The median time tofirst exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8)in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the SPIRIVAHANDIHALER group.

All-Cause Mortality

In the 4-year placebo-controlledlung-function trial described above, all-cause mortality comparedto placebo was assessed. There were no significant differences inall-cause mortality rates between Tiova HANDIHALER and placebo.

The all-cause mortality ofSPIRIVA HANDIHALER was also compared to Tiova inhalation spray5 mcg (SPIRIVA RESPIMAT 5 mcg) in an additional long-term, randomized,double-blind, double-dummy active-controlled study with an observationperiod up to 3 years. All-cause mortality was similar between SPIRIVAHANDIHALER and Tiova RESPIMAT.

Figure 1 Figure 2 Figure 3

16  HOW SUPPLIED/STORAGEAND HANDLING

SPIRIVAHANDIHALER consists of Tiova capsules and the HANDIHALER device. SPIRIVA capsules contain 18 mcg of Tiova and are light green,with the Boehringer Ingelheim company logo on the Tiova capsulecap and TI 01 on the Tiova capsule body, or vice versa.

The HANDIHALER device is gray colored witha green piercing button. It is imprinted with Tiova HANDIHALER (tiotropiumbromide inhalation powder), the Boehringer Ingelheim company logo. It is also imprinted to indicate that Tiova capsules should notbe stored in the HANDIHALER device and that the HANDIHALER deviceis only to be used with Tiova capsules.

Tiova capsules are packaged in an aluminum/aluminumblister card and joined along a perforated-cut line. Tiova capsulesshould always be stored in the blister and only removed immediatelybefore use. The drug should be used immediately after the packagingover an individual Tiova capsule is opened.

The following packages are available:

• carton containing 5 Tiova capsules (1 unit-dose blistercard) and 1 HANDIHALER inhalation device (NDC 0597-0075-75) (institutionalpack)
• carton containing 30 SPIRIVA capsules (3 unit-dose blistercards) and 1 HANDIHALER inhalation device (NDC 0597-0075-41)
• carton containing 90 SPIRIVA capsules (9 unit-dose blistercards) and 1 HANDIHALER inhalation device (NDC 0597-0075-47)

Keep out of reach ofchildren. Do not get powder into eyes.

Storage

Store at 25°C (77°F); excursions permitted to 15°to 30°C (59° to 86°F).

The Tiova capsules should not be exposedto extreme temperature or moisture. Do not store Tiova capsulesin the HANDIHALER device.

17  PATIENT COUNSELING INFORMATION

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

ParadoxicalBronchospasm:

Inform patients that SPIRIVAHANDIHALER can produce paradoxical bronchospasm. Advise patients thatif paradoxical bronchospasm occurs, patients should discontinue SPIRIVAHANDIHALER.

Worsening of Narrow-Angle Glaucoma:

Instruct patients to be alert for signs and symptoms of narrow-angleglaucoma (e.g., eye pain or discomfort, blurred vision, visual halosor colored images in association with red eyes from conjunctival congestionand corneal edema). Instruct patients to consult a physician immediatelyshould any of these signs and symptoms develop.

Inform patients that care must be takennot to allow the powder to enter into the eyes as this may cause blurringof vision and pupil dilation.

Since dizziness and blurred vision may occurwith the use of Tiova HANDIHALER, caution patients about engagingin activities such as driving a vehicle or operating appliances ormachinery.

Worsening of Urinary Retention:

Instruct patients to be alert for signs and symptoms of urinaryretention (e.g., difficulty passing urine, painful urination). Instructpatients to consult a physician immediately should any of these signsor symptoms develop.

Not for Acute Use:

Instruct patients that Tiova HANDIHALER is a once-daily maintenancebronchodilator and should not be used for immediate relief of breathingproblems (i.e., as a rescue medication).

Instructions for AdministeringSPIRIVA HANDIHALER:

Instruct patients on how to correctly administerSPIRIVA capsules using the HANDIHALER device . Instruct patients that Tiova capsules should only be administeredvia the HANDIHALER device and the HANDIHALER device should not beused for administering other medications. Remind patients thatthe contents of Tiova capsules are for oral inhalation only andmust not be swallowed.

Instruct patients always to store SPIRIVAcapsules in sealed blisters and to remove only one Tiova capsuleimmediately before use or its effectiveness may be reduced. Instructpatients to discard unused additional Tiova capsules that are exposedto air (i.e., not intended for immediate use).

Distributed by:

Boehringer Ingelheim Pharmaceuticals,Inc.

Ridgefield, CT 06877 USA

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

SPIRIVA® and HANDIHALER® are registered trademarks andare used under license from Boehringer Ingelheim International GmbH.

Copyright © 2016 Boehringer Ingelheim InternationalGmbH

ALL RIGHTS RESERVED

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Patient Information

Tiova^® (speh REE vah) HANDIHALER^®

(tiotropium bromide inhalation powder)

Do NOT swallowSPIRIVA capsules.

ImportantInformation: Do notswallow Tiova capsules. Tiova capsules should only be used withthe HANDIHALER device and inhaled through your mouth (oral inhalation).

Read the informationthat comes with your Tiova HANDIHALER before you start using itand each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor aboutyour medical condition or your treatment.

What is Tiova HANDIHALER?

• Tiova HANDIHALER is a prescription medicine used eachday (a maintenance medicine) to control symptoms of chronic obstructivepulmonary disease (COPD), including chronic bronchitis and emphysema.
• Tiova HANDIHALER helps make your lungs work better for24 hours. Tiova HANDIHALER relaxes your airways and helps keep themopen. You may start to feel like it is easier to breathe on the firstday, but it may take longer for you to feel the full effects of themedicine. Tiova HANDIHALER works best and may help make it easierto breathe when you use it every day.
• Tiova HANDIHALER reduces the likelihood of flare-ups andworsening of COPD symptoms (COPD exacerbations). A COPD exacerbationis defined as an increase or new onset of more than one COPD symptomsuch as cough, mucus, shortness of breath, and wheezing that requiresmedicine beyond your rescue medicine.

Tiova HANDIHALERis not a rescue medicine and should not be used for treating suddenbreathing problems. Your doctor may give you othermedicine to use for sudden breathing problems.

It is not known if Tiova HANDIHALER is safe and effectivein children.

Whoshould not take Tiova HANDIHALER?

Do not use Tiova HANDIHALER if you:

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

Symptoms of a serious allergic reactionto Tiova HANDIHALER may include:

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

If you have these symptoms of anallergic reaction, stop taking Tiova HANDIHALER and call your doctorright away or go to the nearest hospital emergency room.

What should I tell my doctorbefore using Tiova HANDIHALER?

Before taking Tiova HANDIHALER, tellyour doctor about all your medical conditions, including if you:

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

Tell your doctorabout all the medicines you take, including prescriptionand non-prescription medicines and eye drops, vitamins, and herbalsupplements. Some of your other medicines or supplements may affectthe way Tiova HANDIHALER works. Tiova HANDIHALER is an anticholinergicmedicine. You should not take other anticholinergic medicines whileusing Tiova HANDIHALER, including ipratropium. Ask your doctor orpharmacist if you are not sure if one of your medicines is an anticholinergic.

Know the medicines you take. Keep a listof your medicines with you to show your doctor and pharmacist whenyou get a new medicine.

How should I take Tiova HANDIHALER?

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

What should I avoidwhile using Tiova HANDIHALER?

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

What are the possibleside effects of Tiova HANDIHALER?

Tiova HANDIHALER can cause seriousside effects, including: Allergic reaction. Symptomsmay include:

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

If you have these symptoms of anallergic reaction, stop taking Tiova HANDIHALER and call your doctorright away or go to the nearest hospital emergency room.

• Sudden narrowing and blockage of the airwaysinto the lungs (bronchospasm). Your breathing suddenlygets worse.

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

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

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

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

If you have these symptoms of urinaryretention, stop taking Tiova HANDIHALER and call your doctor rightaway.

Other side effects withSPIRIVA HANDIHALER include:

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

These are not all the possible sideeffects with Tiova HANDIHALER. Tell your doctor if you have anyside effect that bothers you or that does not go away.

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

How do I store SPIRIVAHANDIHALER?

• Do not store Tiova capsules in the HANDIHALERdevice.
• Store Tiova capsules in the sealed blister package atroom temperature between 68°F to 77°F (20°C to 25°C).
• Keep Tiova capsules away from heat and cold (do not freeze).
• Store Tiova capsules in a dry place. Throw away any unusedSPIRIVA capsules that have been open to air.

Ask your doctor or pharmacist ifyou have any questions about storing your Tiova capsules.

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

Generalinformation about Tiova HANDIHALER

Medicinesare sometimes prescribed for purposes other than those listed in PatientInformation leaflets. Do not use Tiova HANDIHALER for a purposefor which it has not been prescribed. Do not give Tiova HANDIHALERto other people even if they have the same symptoms that you have. It may harm them.

For more informationabout Tiova HANDIHALER, talk with your doctor. You can ask yourdoctor or pharmacist for information about Tiova HANDIHALER thatis written for health professionals.

For more information about Tiova HANDIHALER, go to www. SPIRIVA.com, or scan the code below, or call BoehringerIngelheim Pharmaceuticals, Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.

What are the ingredients in Tiova HANDIHALER?

Active ingredient: Tiova

Inactive ingredient: lactose monohydrate

What is COPD (Chronic Obstructive PulmonaryDisease)?

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

This Patient Information has been approved by the U.S.Food and Drug Administration.

Distributed by:

Boehringer Ingelheim Pharmaceuticals,Inc.

Ridgefield, CT 06877 USA

Licensed from:

Boehringer Ingelheim InternationalGmbH

Tiova^® and HANDIHALER^® are registered trademarksand are used under license from Boehringer Ingelheim InternationalGmbH.

Copyright © 2016 BoehringerIngelheim International GmbH

ALL RIGHTS RESERVED

Revised: January 2016

IT1600AGA72016

10004551/13

IT5300J

75740-09

Instructions for Use

SPIRIVA® (speh REEvah) HANDIHALER®

(tiotropium bromide inhalationpowder)

Do not swallowSPIRIVA capsules.

Important Informationabout using your Tiova HANDIHALER

• Do not swallow Tiova capsules.
• Tiova capsules should only be used withthe HANDIHALER device and inhaled through your mouth (oral inhalation).
• Do not use your HANDIHALER device to takeany other medicine.

First read the Patient Information,then read these Instructions for Use before you start to use SPIRIVAHANDIHALER and each time you refill your prescription. There may benew information.

Becoming familiar with your HANDIHALER device and Tiova capsules:

Your Tiova HANDIHALERcomes with Tiova capsules in blister packaging and a HANDIHALERdevice. Use the new HANDIHALER device provided with your medicine.

	The partsof your HANDIHALER device include: (SeeFigure A) dust cap (lid) mouthpiece mouthpiece ridge base green piercing button center chamber air intake vents
	Each Tiova capsule ispackaged in a blister.
	Each Tiova capsule contains only a small amount of powder. This is 1 full dose. Do not open the Tiova capsule or it may not work.
Taking your full dailydose of medicine requires 4 main steps. Step1. Opening your HANDIHALER device:
	After removing your HANDIHALERdevice from the pouch: Open the dust cap (lid) by pressing the green piercing button.
	Pull the dust cap (lid) upwards away from the base to exposethe mouthpiece.
	Open the mouthpiece by pulling the mouthpiece ridge up andaway from the base so the center chamber is showing.
Step 2. Inserting theSPIRIVA capsule into your HANDIHALER device:
	Each day, separate only1 of the blisters from the blister card by tearing along the perforatedline.
	Remove theSPIRIVA capsule from the blister: Do not cut the foil oruse sharp instruments to take out the Tiova capsule from the blister. Bend 1 of the blister corners with an arrow and separatethe aluminum foil layers. Peel back the printed foil until you see the whole SPIRIVAcapsule. If you have opened more than 1 blister to the air, the extraSPIRIVA capsule should not be used and should be thrown away.
	Place the Tiova capsulein the center chamber of your HANDIHALER device.
	Close the mouthpiece firmlyagainst the gray base until you hear a click. Leave the dust cap (lid)open.
Step 3. Piercing the SPIRIVAcapsule:
	Hold your HANDIHALER device with the mouthpiece pointedup. Press the green piercing button once until it is flat (flush)against the base, then release. This is how you make holes in theSPIRIVA capsule so that you get your medicine when you breathe in. Do not press the greenbutton more than one time. Do not shake your HANDIHALERdevice. The piercing of the Tiova capsule may produce small gelatinpieces. Some of these small pieces may pass through the screen ofyour HANDIHALER device into your mouth or throat when you breathein your medicine. This is normal. The small pieces of gelatin shouldnot harm you.
Step 4. Taking your fulldaily dose (2 inhalations from the same Tiova capsule):
	Breatheout completely in 1 breath, emptying your lungsof any air. Important: Do not breathe into your HANDIHALERdevice.
	With yournext breath, take your medicine: Hold your head in an upright position whileyou are looking straight ahead. Raise your HANDIHALER device to your mouth in a horizontalposition. Do not block the air intakevents. Close your lips tightly around the mouthpiece. Breathe in deeply untilyour lungs are full. You should hear or feel the SPIRIVAcapsule vibrate (rattle). Hold your breath for a few seconds and, at the same time,take your HANDIHALER device out of your mouth. Breathe normally again. The rattle tells you that you breathed in correctly. If you do not hear or feel a rattle, see the section, “If you do nothear or feel the Tiova capsule rattle as you breathe in your medicine."
	To get yourfull daily dose, you must again, breathe out completely and for a second time, breathe in from the sameSPIRIVA capsule. Important: Do not press the green piercing buttonagain.
	Remember: To get your full medicine dose each day, you must breathein 2 times from the same Tiova capsule. Make sure you breathe outcompletely each time before you breathe in from your HANDIHALER device.
Caring forand storing your Tiova HANDIHALER:
	After taking your daily dose, open the mouthpiece and tipout the used Tiova capsule into your trash can, without touchingit. Remove any Tiova capsule pieces or Tiova powder buildupby turning your HANDIHALER device upside down and gently, but firmly,tapping it. Then, close the mouthpiece and dustcapfor storage. Do not store your HANDIHALERdevice and Tiova capsules (blisters) in a damp moist place. Alwaysstore Tiova capsules in the sealed blisters.
If you do nothear or feel the Tiova capsule rattle as you breathe in your medicine:
	Do not press the green piercing button again. Hold your HANDIHALER device with the mouthpiece pointed up andtap your HANDIHALER device gently on a table. Check to see that the mouthpiece is completely closed. Breathe out completely before deeply breathing in again with the mouthpiecein your mouth. If you stilldo not hear or feel the Tiova capsule rattle after repeating theabove steps: Throw away the Tiova capsule. Open the base by lifting the green piercing button and checkthe center chamber for pieces of the Tiova capsule. Tiova capsulepieces in the center chamber can cause a Tiova capsule not to rattle. Turn your HANDIHALER device upside down and gently, butfirmly, tap to remove the Tiova capsule pieces. Call your doctorfor instructions.
Cleaning yourHANDIHALER device:
	Clean your HANDIHALER deviceas needed. It takes 24 hours to air dry your HANDIHALERdevice after you clean it. Do not use cleaning agentsor detergents. Do not place your HANDIHALERdevice in the dishwasher for cleaning. Cleaning Steps: Open the dust cap and mouthpiece. Open the base by lifting the green piercing button. Look in the center chamber for Tiova capsule pieces orpowder buildup. If seen, tap out. Rinse your HANDIHALER device with warm water, pressing thegreen piercing button a few times so that the center chamber and thepiercing needle is under the running water. Check that any powderbuildup or Tiova capsule pieces are removed. Dry your HANDIHALER device well by tipping the excess waterout on a paper towel. Air-dry afterwards, leaving the dust cap, mouthpiece,and base open by fully spreading it out so that it dries completely. Do not use a hair dryerto dry your HANDIHALER device. Do not use your HANDIHALERdevice when it is wet. If needed, you may clean the outside of themouthpiece with a clean damp cloth.

Helpful Hints to help ensure that you are properly taking your full dailydose of Tiova HANDIHALER: Press the green piercingbutton 1 time; Breathe in 2 times; Breathe out completely before each of the 2 inhalations. Always use the new HANDIHALER device provided with yourmedicine. Keep your HANDIHALER device with the mouthpiece pointedup when pressing the green piercing button. Press the green piercing button 1 time to pierce the Tiova capsule. Do not breathe out into your HANDIHALER device. Keep your HANDIHALER device in a horizontal position andkeep your head upright, looking straight ahead, when breathing in. Check the center chamber of your HANDIHALER device for SPIRIVAcapsule pieces or powder build-up. If pieces or powder are seen, tapout before use. Clean your HANDIHALER as needed and dry thoroughly.

For more information, ask your doctoror pharmacist, or go to www.spiriva.com, orscan the code below, or call 1-800-542-6257 or (TTY) 1-800-459-9906.

This Instructions for Use has been approved by the U.S. Food andDrug Administration.

Distributedby:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Licensedfrom:

Boehringer Ingelheim International GmbH

SPIRIVA® and HANDIHALER® are registeredtrademarks and are used under license from Boehringer Ingelheim InternationalGmbH.

Copyright © 2016 BoehringerIngelheim International GmbH

ALL RIGHTS RESERVED

Revised: January 2016

IT1600AGA72016

10004551/13

IT5300J

75740-09

SCAN HERE SCAN HERE Instructions for Tiova Instructions for Tiova Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P Figure Q Figure R Tiova HandiHaler

30 capsules (3 blister cards)

1 HandiHaler InhalationDevice

NDC 0597-0075-41

spiriva-hh-ndc-0597-0075-41 Tiova HandiHaler

90 capsules(9 blister cards)

1 HandiHaler Inhalation Device

NDC 0597-0075-47

spiriva-hh-ndc-0597-0075-47 Tiova HandiHaler

5 capsules(1 blister card)

1 HandiHaler Inhalation Device

NDC 0597-0075-75

spiriva-hh-ndc-0597-0075-75 Tiova HandiHaler

ProfessionalSample

10 capsules (1 blister card)

1 HandiHalerInhalation Device

NDC 0597-0075-27

spiriva-hh-ndc-0597-0075-27

Tiova pharmaceutical active ingredients containing related brand and generic drugs:

• Tiotropium Bromide Monohydrate

Tiova available forms, composition, doses:

• Capsules; Inhalation; Tiotropium Bromide Monohydrate 18 mcg

Tiova destination | category:

• Human:
• Antiasthmatic and COPD preparations
• Antimuscarinics antispasmodics

Tiova Anatomical Therapeutic Chemical codes:

• R03BB04 - Tiotropium Bromide

Tiova pharmaceutical companies:

• Cipla

References

1. "Tiotropium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
2. "Tiotropium". http://www.drugbank.ca/drugs/DB0140... (accessed August 28, 2018).
3. "0EB439235F: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Tiova?

Depending on the reaction of the Tiova after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tiova not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Tiova addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Tiova, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tiova consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology