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How To Use Your HandiHaler

1. e Close your lips tightly around the mouthpiece e Breathe in deeply until your lungs are full You should hear or feel the SPIRIVA capsule vibrate rattle See Figure M e Hold your breath for a few seconds and at the same time take your HandiHaler device out of your mouth e Breathe normally again iB Figure M The rattle tells you that you breathed in correctly If you do not hear or feel a rattle see the section If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine To get your full daily dose you must again breathe out completely See Figure N and for a second time breathe in See Figure 0 from the same SPIRIVA capsule Important Do not press the green piercing button again Figure N Remember To get your full medicine dose each day you must breathe in 2 times from the same SPIRIVA capsule Make sure you breathe out completely each time before you breathe in from your HandiHaler device Figure 0 Caring for and storing your SPIRIVA HandiHaler e After taking your daily dose open the mouthpiece and tip out the used SPIRIVA capsule into your trash can without touching it e Remove any SPIRIVA capsule pieces or SPIRIVA powder buildup by turning your HandiHaler device upside down and gently but firmly tapping it See Figure P Then close the mouthpiece and dustcap for storage e Do not store your HandiHaler device and SPIRIVA ca
2. If you have these symptoms of an allergic reaction stop taking SPIRIVA HandiHaler and call your doctor right away or go to the nearest hospital emergency room What should tell my doctor before using SPIRIVA HandiHaler Before taking SPIRIVA HandiHaler tell your doctor about all your medical conditions including if you e have kidney problems e have glaucoma SPIRIVA HandiHaler may make your glaucoma worse e have an enlarged prostate problems passing urine or a blockage in your bladder SPIRIVA HandiHaler may make these problems worse e are pregnant or plan to become pregnant It is not known if SPIRIVA HandiHaler could harm your unborn baby e are breast feeding or plan to breast feed It is not known if SPIRIVA HandiHaler passes into breast milk You and your doctor will decide if SPIRIVA HandiHaler is right for you while you breast feed e have a severe allergy to milk proteins Ask your doctor if you are not sure Tell your doctor about all the medicines you take including prescription and non prescription medicines and eye drops vitamins and herbal supplements Some of your other medicines or supplements may affect the way Spiriva HandiHaler tiotropium bromide inhalation powder 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 medici
3. 2986 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day The population had an age range from 40 to 88 years was 75 male 90 Caucasian and had COPD with a mean pre bronchodilator FEV percent predicted of 40 Patients with narrow angle glaucoma or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials When the adverse reactions were analyzed with a frequency of gt 3 in the SPIRIVA HandiHaler group where the rates in the SPIRIVA 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 Additional Adverse Reactions Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with SPIRIVA HandiHaler than placebo 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 worldwide post approval use of SPIRIVA HandiHaler Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure These adverse react
4. Metabolism The extent of metabolism appears to be small This is evident from a urinary excretion of 74 of unchanged substance after an intravenous dose to young healthy volunteers Tiotropium an ester is nonenzymatically cleaved to the alcohol W methylscopine and dithienylglycolic acid neither of which binds to muscarinic receptors In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose 74 of an intravenous dose is excreted unchanged in the urine leaving 25 for metabolism is metabolized by cytochrome P450 dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors such as quinidine ketoconazole and gestodene Thus CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose n vitro studies using human liver microsomes showed that tiotropium in supra therapeutic concentrations did not inhibit CYP450 1A1 1A2 2B6 2C9 2019 2D6 2E1 or 3A4 Elimination The terminal elimination half life of tiotropium was between 5 and 6 days following inhalation Total clearance was 880 mL min after an intravenous dose in young healthy volunteers with an inter individual variability of 22 Intravenously administered tiotropium was mainly excreted unchanged in urine 74 After dry powder inhalation
5. o blurred vision o seeing halos visual halos or colored images along with red eyes Using only eye drops to treat these symptoms may not work If you have these symptoms stop taking SPIRIVA HandiHaler and call your doctor right away e New or worsened urinary retention Symptoms of blockage in your bladder and or enlarged prostate may include difficulty passing urine painful urination If you have these symptoms of urinary retention stop taking SPIRIVA HandiHaler and call your doctor right away Other side effects with SPIRIVA HandiHaler include e upper respiratory tract infection e indigestion e dry mouth e runny nose e sinus infection e constipation e sore throat e increased heart rate e non specific chest pain e blurred vision e urinary tract infection 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 e Do not store SPIRIVA capsules in the HandiHaler device e Store SPIRIVA capsules in the sealed blister package at room temperature between 68 F to 77 F 20 to 25 C e Keep SPIRIVA capsules away from heat and cold do not freeze e Store SPIRIVA capsules in a dry place Throw away any unused SPIRIVA capsules that have been open to air Ask your doctor or pharmacist if y
6. a site specific effect 12 2 Pharmacodynamics Cardiovascular Effects In a multicenter randomized double blind trial that enrolled 198 patients with COPD the number of subjects with changes from baseline corrected QT interval of 30 to 60 msec was higher in the SPIRIVA HandiHaler group as compared with placebo This difference was appar ent 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 had either QTcB or QTcF of gt 500 msec Other clinical studies with SPIRIVA HandiHaler did not detect an effect of the drug on QTc intervals The effect of SPIRIVA HandiHaler on QT interval was also evaluated in a randomized placebo and positive controlled crossover study in 53 healthy volunteers Subjects received SPIRIVA HandiHaler 18 mcg 54 mcg 3 times the recommended dose or placebo for 12 days ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication Relative to placebo the maximum mean change from base line in study specific QTc interval was 3 2 msec and 0 8 msec for SPIRIVA HandiHaler 18 mcg and 54 mcg respectively No subject showed a new onset of QTc gt 500 msec or QTc changes from baseline of gt 60 msec 12 3 Pharmacokinetics Tiotropium is administered by dry powder inhalation In common with other inhaled drugs the majority
7. for the reduction of COPD exacerbations COPD does not normally occur in children The safety and effectiveness of SPIRIVA HandiHaler in pediatric patients have not been established 8 5 Geriatric Use Of the total number of patients who received Spiriva HandiHaler tiotropium bromide inhalation powder in the 1 year clinical trials 426 were lt 65 years 375 were 65 to 74 years and 105 were 75 years of age Within each age subgroup there were no differences between the proportion of patients with adverse events in the SPIRIVA HandiHaler and the comparator groups for most events Dry mouth increased with age in the SPIRIVA HandiHaler group differ ences from placebo were 9 0 17 1 and 16 2 in the aforementioned age subgroups A higher frequency of constipation and urinary tract infections with increasing age was observed in the SPIRIVA HandiHaler group in the placebo controlled studies The differences from placebo for constipation were 0 1 8 and 7 8 for each of the age groups The differences from placebo for urinary tract infections were 0 6 4 6 and 4 5 No overall differences in effectiveness were observed among these groups Based on available data no adjustment of SPIRIVA HandiHaler dosage in geriatric patients is warranted see Clinical Pharmacology 12 3 8 6 Renal Impairment Patients with moderate to severe renal impairment creatinine clearance of lt 50 mL min treated with SPIRIVA HandiHaler should be monitored cl
8. inhalation tiotropium doses of up to approximately 660 and 6 times the recommended 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 a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg m basis In rabbits tiotropium caused an increase in post implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg m basis Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg m basis in rats and rabbits respectively These dose multiples may be over estimated due to difficulties in measuring deposited doses in animal inhalation studies 8 2 Labor and Delivery The safety and effectiveness of SPIRIVA HandiHaler has not been studied during labor and delivery 8 3 Nursing Mothers Clinical data from nursing women exposed to tiotropium are not available Based on lactating rodent studies tiotropium is excreted into breast milk It is not known whether tiotropium is excreted in human milk but because many drugs are excreted in human milk and given these findings in rats caution should be exercised if SPIRIVA HandiHaler is administered to a nursing woman 8 4 Pediatric Use SPIRIVA HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and
9. the HandiHaler device see Patient Counseling Information 17 For administration of SPIRIVA HandiHaler a SPIRIVA capsule is placed into the center chamber of the HandiHaler device The SPIRIVA capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device The tiotropium formulation is dispersed into 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 severe renal impairment given SPIRIVA HandiHaler should be monitored closely for anticholinergic effects see Warnings and Precautions 5 6 Use in Specific Populations 8 5 8 6 8 7 and Clinical Pharmacology 12 3 3 DOSAGE FORMS AND STRENGTHS SPIRIVA HandiHaler consists of SPIRIVA capsules and a HandiHaler device SPIRIVA capsules contain 18 mcg dry powder formulation of tiotropium in a light green hard gelatin capsule with TI 01 printed on one side and Boehringer Ingelheim company logo on the other side 4 CONTRAINDICATIONS SPIRIVA HandiHaler is contraindicated in patients with a hypersensitivity to tiotropium ipratropium or any components of SPIRIVA capsules see WARNINGS AND PRECAUTIONS 5 2 In clinical trials and postmarketing experience with SPIRIVA HandiHaler immediate hypersensi tivity reactions including angioedema including swelling of the l
10. time every 24 hours If you use more than your prescribed dose of SPIRIVA HandiHaler call your doctor or a poison control center What should I avoid while using SPIRIVA HandiHaler e 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 e SPIRIVA HandiHaler can cause dizziness and blurred vision Should you experience these symptoms you should use caution when engaging in activities such as driving a car or operating appliances or other machines What are the possible side effects of SPIRIVA HandiHaler SPIRIVA HandiHaler can cause serious side effects including Allergic reaction Symptoms may include o raised red patches on your skin hives o itching o rash o swelling of the lips tongue or throat that may cause difficulty in breathing or swallowing If you have these symptoms of an allergic reaction stop taking SPIRIVA HandiHaler and call your doctor right away or go to the nearest hospital emergency room e Sudden narrowing and blockage of the airways into the lungs bronchospasm Your breathing suddenly gets worse If you have these symptoms of bronchospasm stop taking SPIRIVA HandiHaler and call your doctor right away or go to the nearest hospital emergency room e New or worsened increased pressure in the eyes acute narrow angle glaucoma Symptoms of acute narrow angle glaucoma may include o eye pain
11. your HandiHaler device See Figure Close the mouthpiece firmly against the gray base until you hear a click Leave the dust cap lid open See Figure J Figure J Step 3 Piercing the SPIRIVA capsule e Hold your HandiHaler device with the mouthpiece pointed up See Figure K e Press the green piercing button once until it is flat flush against the base then release This is how you make holes in the SPIRIVA capsule so that you get your medicine when you breathe in e Do not press the green button more than one time e Do not shake your HandiHaler device e The piercing of the SPIRIVA capsule may produce small gelatin pieces Some of these small pieces may pass through the screen of your HandiHaler device into your mouth or throat when you breathe in your medicine This is normal The small pieces of gelatin should not harm you Figure K Step 4 Taking your full daily dose 2 inhalations from the same Spiriva HandiHaler tiotropium bromide inhalation powder capsule Breathe out completely in 1 breath emptying your lungs of any air See Figure L gt Important Do not breathe into your HandiHaler device Figure L With your next breath take your medicine e Hold your head in an upright position while you are looking straight ahead See Figure M e Raise your HandiHaler device to your mouth in a horizontal position Do not block the air intake vents
12. 2 For Oral Inhalation ONLY 2 e Two inhalations of the powder contents of a single SPIRIVA capsule 18 mcg once daily 2 DOSAGE FORMS AND STRENGTHS SPIRIVA capsules for oral inhalation 18 mcg tiotropium powder for use with HandiHaler device 3 CONTRAINDICATIONS e Hypersensitivity to tiotropium ipratropium or any components of SPIRIVA capsules 4 WARNINGS AND PRECAUTIONS e Not for acute use Not for use as a rescue medication 5 1 e Immediate hypersensitivity reactions Discontinue SPIRIVA HandiHaler at once and consider alternatives if immediate hypersensitivity reactions including angioedema bronchospasm or anaphylaxis occur Use with caution in patients with severe hypersensitivity to milk proteins 5 2 e Paradoxical bronchospasm Discontinue SPIRIVA HandiHaler and consider other treatments if paradoxical bronchospasm occurs 5 3 e Worsening of narrow angle glaucoma may occur Use with caution in patients with narrow angle glaucoma and instruct patients to consult a physician immediately if this occurs 5 4 e Worsening of urinary retention may occur Use with caution in patients with prostatic hyper plasia or bladder neck obstruction and instruct patients to consult a physician immediately if this occurs 5 5 ADVERSE REACTIONS e The most common adverse reactions gt 5 incidence in the 1 year placebo controlled trials were upper respiratory tract infection dry mouth sinusitis pharyngitis non
13. L SPIRIVA Handler How To Use Your HandiHaler It s important to remember to take SPIRIVA every day and use your SPIRIVA HandiHaler correctly as prescribed by your doctor This quick overview may help For complete information on using the SPIRIVA HandiHaler please see the Instructions for Use attached to your SPIRIVA HandiHaler prescription Familiarize yourself with the parts of your HandiHaler device Dust cap lid Mouthpiece Mouthpiece ridge Base Green piercing button Center chamber Air intake vents 1 Open the HandiHaler device Separate only one of the blisters from the blister card then open the blister 2 Insert the SPIRIVA capsule and close the mouthpiece firmly against the gray base until you hear a click 3 Press the green piercing button once until it is flat flush against the base then release 4 Breathe out completely Then with the HandiHaler in your mouth breathe in deeply until your lungs are full You should hear or feel the SPIRIVA capsule vibrate rattle Remember to take your full daily dose you must inhale twice from the same SPIRIVA capsule Important information about using your SPIRIVA HandiHaler e Do not swallow SPIRIVA capsules e SPIRIVA capsules should only be used with the HandiHaler device and inhaled through your mouth oral inhalation e Do not use your HandiHaler device to take any other medicine IMPORTANT SAFETY INFORMATION Do not use Spiriv
14. RIVA capsule contains only a small amount of powder See Figure C This is 1 full dose e Do not open the SPIRIVA capsule or it may not work Figure B Amount of 5 powder in the SPIRIVA capsule Figure C Taking your full daily dose of medicine requires 4 main steps Step 1 Opening your HandiHaler device After removing your HandiHaler device from the pouch e Open the dust cap lid by pressing the green piercing button See Figure D e Pull the dust cap lid upwards away from the base to expose the mouthpiece See Figure E Figure E e Open the mouthpiece by pulling the mouthpiece ridge LS up and away from the base so the center chamber is showing See Figure F Figure F Step 2 Inserting the SPIRIVA capsule into your HandiHaler device Each day separate only 1 of the blisters from the blister card by tearing along the perforated line See Figure G Remove the SPIRIVA capsule from the blister e Do not cut the foil or use sharp instruments to take out the SPIRIVA capsule from the blister e Bend 1 of the blister corners with an arrow and separate the aluminum foil layers e Peel back the printed foil until you see the whole SPIRIVA capsule See Figure H e f you have opened more than 1 blister to the air the extra SPIRIVA capsule should not be used and should be thrown away Figure H Place the SPIRIVA capsule in the center chamber of
15. T 06877 USA Licensed from Boehringer Ingelheim International GmbH SPIRIVA and HandiHaler are registered trademarks and are used under license from Boehringer Ingelheim International GmbH Copyright 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised April 2014 IT1600AED292014 10004551 12 IT5300H 75740 08 Instructions for Use SPIRIVA Speh REE vah HandiHaler tiotropium bromide inhalation powder Do not swallow SPIRIVA capsules Important Information about using your SPIRIVA HandiHaler e Do not swallow SPIRIVA capsules e SPIRIVA capsules should only be used with the HandiHaler device and inhaled through your mouth oral inhalation e Do not use your HandiHaler device to take any other medicine First read the Patient Information then read these Instructions for Use before you start to use SPIRIVA HandiHaler and each time you refill your prescription There may be new information Becoming familiar with your HandiHaler device and SPIRIVA capsules Your SPIRIVA HandiHaler comes with SPIRIVA capsules in blister packaging and a HandiHaler device Use the new HandiHaler device provided with your medicine The parts of your HandiHaler device include See Figure A 1 dust cap lid 2 mouthpiece 3 mouthpiece ridge 4 base 5 green piercing button 6 center chamber 7 air intake vents Each SPIRIVA capsule is packaged in a blister See Figure B SRE e Each SPI
16. a HandiHaler tiotropium bromide inhalation powder if you are allergic to tiotropium or ipratropium e g Atrovent or any of the ingredients in SPIRIVA If your breathing suddenly worsens your face throat lips or tongue swells you get hives itching or rash stop taking SPIRIVA and seek immediate medical help SPIRIVA HandiHaler is not a rescue medicine and should not be used for treating sudden breathing problems Do not swallow SPIRIVA capsules The contents of the capsule should only be inhaled through your mouth using the HandiHaler device If you have vision changes or eye pain or if you have difficulty passing urine or painful urination stop taking SPIRIVA and call your doctor right away Tell your doctor if you have glaucoma problems passing urine or an enlarged prostate as these may worsen with SPIRIVA Tell your doctor if you have kidney problems or are allergic to milk proteins Ask your doctor if you are not sure Also discuss with your doctor all the medicines you take including eye drops The most common side effect with SPIRIVA is dry mouth Others include constipation and trouble passing urine For a complete list of reported side effects ask your doctor or pharmacist Read the Patient Information and the step by step Instructions for Use for SPIRIVA before you use your inhaler INDICATION Spiriva HandiHaler tiotropium bromide inhalation powder is a prescription medicine used once each day a mainten
17. aled blisters and to remove only one SPIRIVA capsule immediately before use or its effectiveness may be reduced Instruct patients to discard unused additional SPIRIVA capsules that are exposed to air i e not intended for immediate use 17 2 Paradoxical Bronchospasm Inform patients that SPIRIVA HandiHaler can produce paradoxical bronchospasm Advise patients that if paradoxical bronchospasm occurs patients should discontinue SPIRIVA HandiHaler 17 3 Urinary Retention Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop 17 4 Visual Effects Eye pain or discomfort blurred vision visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow angle glaucoma Inform patients to consult a physician immediately should any of these signs and symptoms develop Advise patients that miotic eye drops alone are not considered to be effective treatment Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation Since dizziness and blurred vision may occur with the use of SPIRIVA HandiHaler caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery 17 5 Acute Exacerba
18. ance medicine to control symptoms of chronic obstructive pulmonary disease COPD by relaxing your airways and keeping them open COPD includes chronic bronchitis emphysema or both SPIRIVA HandiHaler also reduces the likelihood of flare ups and worsening of COPD symptoms COPD exacerbations You are encouraged to report negative side effects of prescription drugs to the FDA Visit www fda gov medwatch or call 1 800 FDA 1088 Please see accompanying full Prescribing Information including Patient Information and Instructions for Use Copyright 2014 Boehringer Ingelheim Pharmaceuticals Inc All rights reserved SV587504CONS 01 14 CN Boehringer lh Ingelheim HIGHLIGHTS OF PRESCRIBING INFORMATION 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 Respiratory Inhalation DO NOT Swallow SPIRIVA Capsules FOR ORAL INHALATION ONLY with the HandiHaler Device Initial U S Approval 2004 INDICATIONS AND USAGE SPIRIVA HandiHaler is an anticholinergic indicated for the long term once daily maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease COPD and for reducing COPD exacerbations 1 DOSAGE AND ADMINISTRATION DO NOT swallow SPIRIVA capsules 2 For Use with the HandiHaler Device ONLY
19. d in the blister and only removed immediately before use The drug should be used immediately after the packaging over an individual SPIRIVA capsule is opened The following packages are available e carton containing 5 SPIRIVA capsules 1 unit dose blister card and 1 HandiHaler inhalation device NDC 0597 0075 75 institutional pack e carton containing 30 SPIRIVA capsules 3 unit dose blister cards and 1 HandiHaler inhalation device NDC 0597 0075 41 e carton containing 90 SPIRIVA capsules 9 unit dose blister cards and 1 HandiHaler inhalation device NDC 0597 0075 47 Storage Store at 25 C 77 F excursions permitted to 15 to 30 C 59 to 86 F see USP Controlled Room Temperature The SPIRIVA capsules should not be exposed to extreme temperature or moisture Do not store SPIRIVA capsules in the HandiHaler device 17 PATIENT COUNSELING INFORMATION See FDA approved Patient Labeling 17 1 Instructions for Administering SPIRIVA HandiHaler It is important for patients to understand how to correctly administer SPIRIVA capsules using the HandiHaler device see Patient Counseling Information 17 Instruct patients that SPIRIVA capsules should only be administered via the HandiHaler device and the HandiHaler device should not be used for administering other medications Remind patients that the contents of SPIRIVA capsules are for oral inhalation only and must not be swallowed Instruct patients always to store SPIRIVA capsules in se
20. e alert for signs and symptoms of acute narrow angle glau coma e g eye pain or discomfort blurred vision visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema Instruct patients to consult a physician immediately should any of these signs or symptoms develop 5 5 Worsening of Urinary Retention SPIRIVA HandiHaler should be used with caution in patients with urinary retention Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder neck obstruction e g difficulty passing urine painful urination Instruct patients to consult a physician immediately should any of these signs or symptoms develop 5 6 Renal Impairment As a predominantly renally excreted drug patients with moderate to severe renal impairment creatinine clearance of lt 50 mL min treated with SPIRIVA HandiHaler should be monitored closely for anticholinergic side effects see Clinical Pharmacology 12 3 6 ADVERSE REACTIONS The following adverse reactions are described or described in greater detail in other sections e Immediate hypersensitivity reactions see Warnings and Precautions 5 2 e Paradoxical bronchospasm see Warnings and Precautions 5 3 e Worsening of narrow angle glaucoma see Warnings and Precautions 5 4 e Worsening of urinary retention see Warnings and Precautions 5 5 6 1 Clinical Trials Experience Because Clinical trials are conducted under widely
21. eactions that occurred in the SPIRIVA HandiHaler group at a frequency of 1 to 3 in the placebo controlled trials 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 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 reactions observed in the clinical trials with an incidence of lt 1 were atrial fibrillation supraventricular tachycar dia angioedema and urinary retention In the 1 year trials the incidence of dry mouth constipation and urinary tract infection increased with age see Use in Specific Populations 8 5 Two multicenter 6 month controlled studies evaluated SPIRIVA HandiHaler in patients with COPD The adverse reactions and the incidence rates were similar to those seen in the 1 year controlled trials 4 Year Trial The data described below reflect exposure to SPIRIVA HandiHaler in 5992 COPD patients in a 4 year placebo controlled trial In this trial
22. ed Studies Day 1 Day 92 x eg WSs 4 SPIRIVA n 153 Ipratropium n 72 A SPIRIVA n 153 Ipratropium n 72 2 3 4 5 oa 2 3 4 5 6 Time hours Time hours Means adjusted for center treatment and baseline effect On Day 92 primary endpoint a total of 151 and 69 patients in the SPIRIVA HandiHaler and ipratropium groups respectively completed through 3 months of observation The data for the remaining patients were imputed using the last observation or least favorable observation carried forward A randomized placebo controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether SPIRIVA HandiHaler was administered in the morning or in the evening Throughout each week of the one year treatment period in the two placebo controlled trials patients taking SPIRIVA HandiHaler had a reduced requirement for the use of rescue short acting beta agonists Reduction in the use of rescue short acting beta agonists as compared to placebo was demonstrated 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 conducted to evaluate the long term effects of SPIRIVA HandiHaler on disease progression rate of decline in FEV Patients were permitted to use all respiratory medica
23. halation which was not significant when considered in relation to inter and intra individual variability see Dosage and Administration 2 and Use in Specific Populations 8 5 Renal Impairment Since tiotropium is predominantly renally excreted renal impairment was associated with increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder inhalation Mild renal impairment creatinine clearance of 50 to 80 mL min which is often seen in elderly patients increased tiotropium plasma concentrations 39 increase in AUC after intravenous infusion In COPD patients with moderate to severe renal impairment creatinine clearance of lt 50 mL min the intravenous administration of tiotropium resulted in doubling of the plasma concentrations 82 increase in AUC which was confirmed by plasma concentrations after dry powder inhalation Patients with moderate to severe renal impairment creatinine clearance of lt 50 mL min treated with Spiriva HandiHaler tiotropium bromide inhalation powder should be monitored closely for anticholinergic side effects see Dosage and Administration 2 Warnings and Precautions 5 6 and Use in Specific Populations 8 6 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility No evidence of tumorigenicity wa
24. ions are application site irritation glossitis mouth ulceration and pharyngolaryngeal pain dizziness dysphagia hoarseness intestinal obstruction including ileus paralytic intraocular pressure increased oral candidiasis palpitations pruritus tachycar dia throat irritation and urticaria 7 DRUG INTERACTIONS 7 1 Sympathomimetics Methylxanthines Steroids SPIRIVA HandiHaler has been used concomitantly with short acting and long acting sympatho mimetic beta agonists bronchodilators methylxanthines and oral and inhaled steroids without increases in adverse drug reactions 7 2 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications Therefore avoid coadministration of SPIRIVA HandiHaler with other anticholin ergic containing drugs as this may lead to an increase in anticholinergic adverse effects see Warnings and Precautions 5 4 5 5 and Adverse Reactions 6 7 3 Cimetidine Ranitidine No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine see Clinical Pharmacology 12 3 8 USE IN SPECIFIC POPULATIONS 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 potential benefit justifies the potential risk to the fetus No evidence of structural alterations was observed in rats and rabbits at
25. ips tongue or throat itching or rash have been reported 5 WARNINGS AND PRECAUTIONS 5 1 Not for Acute Use SPIRIVA HandiHaler is intended as a once daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm i e rescue therapy 5 2 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions including urticaria angioedema including swelling of the lips tongue or throat rash bronchospasm anaphylaxis or itching may occur after administra tion of SPIRIVA HandiHaler If such a reaction occurs therapy with SPIRIVA HandiHaler should be stopped at once and alternative treatments should be considered Given the similar structural formula of atropine to tiotropium patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to Spiriva HandiHaler tiotropium bromide inhalation powder In addition SPIRIVA HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins 5 3 Paradoxical Bronchospasm Inhaled medicines including SPIRIVA HandiHaler can produce paradoxical bronchospasm If this occurs treatment with SPIRIVA HandiHaler should be stopped and other treatments considered 5 4 Worsening of Narrow Angle Glaucoma SPIRIVA HandiHaler should be used with caution in patients with narrow angle glaucoma Prescribers and patients should b
26. irment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action 12 2 Pharmacodynamics 12 3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 13 2 Animal Toxicology and Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17 1 Instructions for Administering SPIRIVA HandiHaler 17 2 Paradoxical Bronchospasm 17 3 Urinary Retention 17 4 Visual Effects 17 5 Acute Exacerbation Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SPIRIVA HandiHaler tiotropium bromide inhalation powder is indicated for the long term once daily maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease COPD including chronic bronchitis and emphysema SPIRIVA HandiHaler is indicated to reduce exacerbations in COPD patients 2 DOSAGE AND ADMINISTRATION DO NOT SWALLOW SPIRIVA CAPSULES FOR USE WITH HANDIHALER DEVICE ONLY FOR ORAL INHALATION ONLY SPIRIVA capsules must not be swallowed as the intended effects on the lungs will not be obtained The contents of the SPIRIVA capsules are only for oral inhalation and should only be used with the HandiHaler device see Overdosage 10 The recommended dose of SPIRIVA HandiHaler is two inhalations of the powder contents of one SPIRIVA capsule once daily with
27. lowing respiratory symptoms cough sputum sputum purulence wheezing dyspnea with a duration of three or more days requiring treatment with antibiotics and or systemic oral intramuscular or intravenous steroids SPIRIVA HandiHaler significantly reduced the risk of an exacerbation by 14 Hazard Ratio HR 0 86 95 Cl 0 81 0 91 p lt 0 001 and reduced the risk of exacerbation related hospitalization by 14 HR 0 86 95 Cl 0 78 0 95 p lt 0 002 compared to placebo The median time to first exacerbation was delayed from 12 5 months 95 Cl 11 5 13 8 in the placebo group to 16 7 months 95 Cl 14 9 17 9 in the SPIRIVA HandiHaler group 16 HOW SUPPLIED STORAGE AND HANDLING SPIRIVA HandiHaler consists of SPIRIVA capsules and the HandiHaler device SPIRIVA capsules contain 18 mcg of tiotropium and are light green with the Boehringer Ingelheim company logo on the SPIRIVA capsule cap and TI 01 on the SPIRIVA capsule body or vice versa The HandiHaler device is gray colored with a green piercing button It is imprinted with SPIRIVA HandiHaler tiotropium bromide inhalation powder the Boehringer Ingelheim company logo It is also imprinted to indicate that SPIRIVA capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with SPIRIVA capsules SPIRIVA capsules are packaged in an aluminum aluminum blister card and joined along a perforated cut line SPIRIVA capsules should always be store
28. n Four multicenter 1 year placebo controlled and active controlled trials evaluated SPIRIVA HandiHaler in patients with COPD Table 1 shows all adverse reactions that occurred with a frequency of gt 3 in the SPIRIVA HandiHaler group in the 1 year placebo controlled trials where the rates in the SPIRIVA HandiHaler group exceeded placebo by 21 The frequency of corresponding reactions 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 SPIRIVA Placebo SPIRIVA Ipratropium n 550 n 371 n 356 n 179 Body as a Whole Chest Pain non specific 7 5 5 2 Edema Dependent 5 4 3 5 Gastrointestinal System Disorders 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 like symptoms occurred at a rate of gt 3 in the SPIRIVA HandiHaler treatment group but were lt 1 in excess of the placebo group Other r
29. nes 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 take SPIRIVA HandiHaler Use SPIRIVA HandiHaler exactly as prescribed Use SPIRIVA HandiHaler one time every day e Read the Instructions for Use at the end of this leaflet before you use SPIRIVA HandiHaler Talk with your doctor if you do not understand the instructions Do not swallow SPIRIVA capsules Only use SPIRIVA capsules with the HandiHaler device Do not use the HandiHaler device to take any other medicine SPIRIVA HandiHaler comes as a powder in a SPIRIVA capsule that fits the HandiHaler device Each SPIRIVA capsule containing only a small amount of SPIRIVA powder is one full dose of medicine Separate one blister from the blister card Then take out one of the SPIRIVA capsules from the blister package right before you use it After the capsule is pierced take a complete dose of SPIRIVA HandiHaler by breathing in the powder by mouth two times using the HandiHaler device take 2 inhalations from one SPIRIVA capsule See the Instructions for Use at the end of this leaflet Throw away any SPIRIVA capsule that is not used right away after it is taken out of the blister package Do not leave the SPIRIVA capsules open to air they may not work as well If you miss a dose take it as soon as you remember Do not use SPIRIVA HandiHaler more than one
30. of the delivered dose is deposited in the gastrointestinal tract and to a lesser extent in the lung the intended organ Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy Absorption Following dry powder inhalation by young healthy volunteers the absolute bioavailability of 19 5 suggests that the fraction reaching the lung is highly bioavailable It is expected from the chemical structure of the compound quaternary ammonium compound that tiotropium is poorly absorbed from the gastrointestinal tract The effect of food on tiotropium s bioavailability has not been studied Oral solutions of tiotropium have an absolute bioavailability of 2 to 3 Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation Distribution Tiotropium shows a volume of distribution of 32 L kg indicating that the drug binds extensively to tissues The human plasma protein binding for tiotropium is 72 At steady state peak tiotropium plasma levels in COPD patients were 17 to 19 pg mL when measured 5 minutes after dry powder inhalation of an 18 mcg dose and decreased in a multi compartmental manner Steady state trough plasma concentrations were 3 to 4 pg mL Local concentrations in the lung are not known but the mode of administration suggests substantially higher concen trations in the lung Studies in rats have shown that tiotropium does not readily penetrate the blood brain barrier
31. or SPIRIVA capsule pieces or powder build up If pieces or powder are seen tap out before use Clean your HandiHaler as needed and dry thoroughly For more information ask your doctor or pharmacist or go to www spiriva com or scan the code below or call 1 800 542 6257 This Instructions for Use 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 International GmbH SPIRIVA and HandiHaler are registered trademarks and are used under license from Boehringer Ingelheim International GmbH Copyright 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised April 2014 IT1600AED292014 10004551 12 IT5300H 75740 08 V615902PROF
32. osely 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 the pharmacokinetics of tiotropium were not studied 10 OVERDOSAGE High doses of tiotropium may lead to anticholinergic signs and symptoms However there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers In a study of 12 healthy volunteers bilateral conjunctivitis and dry mouth were seen following repeated once daily inhalation of 141 mcg of tiotropium Accidental Ingestion Acute intoxication by inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is not well absorbed systemically A case of overdose has been reported from postmarketing experience A female patient was reported to have inhaled 30 capsules over a 2 5 day period and developed altered mental status tremors abdominal pain and severe constipation The patient was hospitalized SPIRIVA HandiHaler was discontinued and the constipation was treated with an enema The patient recovered and was discharged on the same day No mortality was observed at inhalation tiotropium doses up to 32 4 mg kg in mice 267 7 mg kg in rats and 0 6 mg kg in dogs These doses correspond to 7300 120 000 and 850 times the recommended human daily inhalation dose on a mg m basis respectively These dose m
33. ou 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 go to www SPIRIVA com or scan the code below or 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 tiotropium Inactive 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 This Patient Information has been approved by the U S Food and Drug Administration Distributed by Boehringer Ingelheim Pharmaceuticals Inc Ridgefield C
34. plex of respiratory symptoms increase or new onset of more than one of the following cough sputum wheezing dyspnea or chest tightness with a duration of at least 3 days requiring treatment with antibiotics systemic steroids or hospitalization The population had an age ranging from 40 to 90 years with 99 males 91 Caucasian and had COPD with a mean pre bronchodilator FEV percent predicted of 36 range 8 to 93 Patients were permitted to use respiratory medications including short acting and long acting beta agonists inhaled and systemic steroids and theophyllines other than inhaled anticholinergics In the 6 month trial the co primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation Spiriva HandiHaler tiotropium bromide inhalation powder significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo 27 9 vs 32 3 respectively Odds Ratio OR tiotropium placebo 0 81 95 Cl 0 66 0 99 p 0 037 The proportion of patients with hospitalization due to COPD exacerbations in patients who used SPIRIVA HandiHaler compared to placebo was 7 0 vs 9 5 respectively OR 0 72 95 Cl 0 51 1 01 p 0 056 Exacerbations were evaluated as a secondary outcome in the 4 year multicenter trial In this trial COPD exacerbations were defined as an increase or new onset of more than one of the fol
35. psules blisters in a damp moist place Always store SPIRIVA capsules in the sealed blisters If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine Figure P Do not press the green piercing button again Hold your HandiHaler device with the mouthpiece pointed up and tap your HandiHaler device gently on a table See Figure Q Check to see that the mouthpiece is completely closed Breathe out completely before deeply breathing in again with the mouthpiece in your mouth See Figure 0 If you still do not hear or feel the SPIRIVA capsule rattle after repeating the above steps e Throw away the SPIRIVA capsule Figure Q e Open the base by lifting the green piercing button and check the center chamber for pieces of the SPIRIVA capsule SPIRIVA capsule pieces in the center chamber can cause a SPIRIVA capsule not to rattle e Turn your HandiHaler device upside down and gently but firmly tap to remove the SPIRIVA capsule pieces Call your doctor for instructions Cleaning your HandiHaler device cq Clean your HandiHaler device as needed See Figure R mi was e It takes 24 hours to air dry your HandiHaler poe device after you clean it e Do not use cleaning agents or detergents e Do not place your HandiHaler device in the al Figure R dishwasher for cleaning Cleaning Steps e Open the dust cap and mouthpiece e Open the base by lif
36. r had a history of smoking greater than 10 pack years had a forced expiratory volume in one second FEV less than or equal to 60 or 65 of predicted and a ratio of FEV FVC of less 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 effect occurring within 3 hours following the first dose Two additional trials evaluated exacerbations a 6 month randomized double blind placebo controlled multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4 year randomized double blind placebo controlled multicenter clinical trial of 5992 COPD patients Long term effects on lung function and other outcomes were also evaluated in the 4 year multicenter trial 6 Month to 1 Year Effects on Lung Function In the 1 year placebo controlled trials the mean improvement in FEV at 30 minutes was 0 13 liters 13 with a peak improvement of 0 24 liters 24 relative to baseline after the first dose Day 1 Further improvements in FEV and forced vital capacity FVC were observed with pharmacodynamic steady state reached by Day 8 with once daily treatment The mean peak improvement in FEV relative to baseline was 0 28 to 0 31 liters 28 to 31 after 1 week Day 8 of once daily treatment Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1 year treatmen
37. s 20 L min Under standardized in vitro testing the HandiHaler device delivers a mean of 10 4 mcg tiotropium 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 lung function mean FEV 1 02 L range 0 45 to 2 24 L 37 6 of predicted range 16 to 65 the median peak inspiratory flow PIF through the HandiHaler device was 30 0 L min range 20 4 to 45 6 L min The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device which may vary from patient to patient and may vary with the exposure time of the SPIRIVA capsule outside the blister pack 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action Tiotropium is a long acting antimuscarinic agent which is often referred to as an anticholin ergic It has similar affinity to the subtypes of muscarinic receptors M to M In the airways it exhibits pharmacological effects through inhibition of M receptors at the smooth muscle leading to bronchodilation The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations In preclinical in vitro as well as in vivo studies prevention of methacholine induced bronchoconstriction effects was dose dependent and lasted longer than 24 hours The bronchodilation following inhalation of tiotropium is predominantly
38. s and emphysema e 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 e SPIRIVA HandiHaler 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 It is not known if SPIRIVA HandiHaler is safe and effective in children Who should not take SPIRIVA HandiHaler Do not use SPIRIVA HandiHaler if you e are allergic to tiotropium ipratropium Atrovent or any of the ingredients in SPIRIVA HandiHaler See the end of this leaflet for a complete list of ingredients in SPIRIVA HandiHaler Symptoms of a serious allergic reaction to SPIRIVA HandiHaler may include o raised red patches on your skin hives o itching o rash o swelling of the face lips tongue and throat that may cause difficulty in breathing or swallowing
39. s observed in a 104 week inhalation study in rats at tiotropium doses up to 0 059 mg kg day in an 83 week inhalation study in female mice at doses up to 0 145 mg kg day and in a 101 week inhalation study in male mice at doses up to 0 002 mg kg day These doses correspond to approximately 25 35 and 0 5 times the recommended human daily inhalation dose RHDID on a mg m basis respectively These dose multiples may be over estimated due to difficulties in measuring deposited doses in animal inhalation studies Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays the bacterial gene mutation assay the V79 Chinese hamster cell mutagenesis assay the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo and the unscheduled DNA synthesis in primary rat hepatocytes jin vitro assay In rats decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 0 078 mg kg day or greater approximately 35 times the RHDID on a mg m basis No such effects were observed at 0 009 mg kg day approximately 4 times than the RHDID on a mg m basis The fertility index however was not affected at inhalation doses up to 1 689 mg kg day approximately 760 times the RHDID on a mg m basis These dose multiples may be over estimated due to difficulties in measuring deposited doses in animal inhalation studies 13 2 Animal To
40. specific chest 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 DRUG INTERACTIONS Anticholinergics May interact additively with concomitantly used anticholinergic medications Avoid administration of SPIRIVA HandiHaler with other anticholinergic containing drugs 7 2 USE IN SPECIFIC POPULATIONS Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects 2 8 6 See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling Revised 04 2014 FULL PRESCRIBING INFORMATION CONTENTS INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5 1 Not for Acute Use 5 2 Immediate Hypersensitivity Reactions 5 3 Paradoxical Bronchospasm 5 4 Worsening of Narrow Angle Glaucoma 5 5 Worsening of Urinary Retention 5 6 Renal Impairment 6 ADVERSE REACTIONS 6 1 Clinical Trials Experience 6 2 Postmarketing Experience 7 DRUG INTERACTIONS 7 1 Sympathomimetics Methylxanthines Steroids 7 2 Anticholinergics 7 3 Cimetidine Ranitidine 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy 8 2 Labor and Delivery 8 3 Nursing Mothers a fF ON 8 4 Pediatric Use 8 5 Geriatric Use 8 6 Renal Impairment 8 7 Hepatic Impa
41. t period with no evidence of tolerance In the two 6 month placebo controlled trials serial spirometric evaluations were performed throughout daytime hours in Trial A 12 hours and limited to 3 hours in Trial B The serial FEV values over 12 hours Trial A are displayed in Figure 1 These trials further support the improvement in pulmonary function FEV with SPIRIVA HandiHaler which persisted over the spirometric observational period Effectiveness was maintained for 24 hours after administration over the 6 month treatment period Figure 1 Mean FEV Over Time prior to and after administration of study drug on Days 1 and 169 for Trial A a Six Month Placebo Controlled Study Day 1 Day 169 4 SPIRIVA n 202 Placebo n 179 4 SPIRIVA n 202 Placebo n 179 e t ote 2 4 6 8 Time hours Means adjusted for center treatment and baseline effect On Day 169 a total of 183 and 149 patients in the SPIRIVA HandiHaler and placebo groups respectively completed the trial The data for the remaining patients were imputed using the last observation or least favorable observation carried forward Results of each of the 1 year ipratropium controlled trials were similar to the results of the 1 year placebo controlled trials The results of one of these trials are shown 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 Two Ipratropium Controll
42. ting the green piercing button e Look in the center chamber for SPIRIVA capsule pieces or powder buildup If seen tap out e Rinse your HandiHaler device with warm water pressing the green piercing button a few times so that the center chamber and the piercing needle is under the running water Check that any powder buildup or SPIRIVA capsule pieces are removed e Dry your HandiHaler device well by tipping the excess water out 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 e Do not use a hair dryer to dry your HandiHaler device e Do not use your HandiHaler device when it is wet If needed you may clean the outside of the mouthpiece with a clean damp cloth Helpful Hints to help ensure that you are properly taking your full daily dose of SPIRIVA HandiHaler e Press the green piercing button 1 time Breathe in 2 times Breathe out completely before each of the 2 inhalations Always use the new HandiHaler device provided with your medicine Keep your HandiHaler device with the mouthpiece pointed up when pressing the green piercing button Press the green piercing button 1 time to pierce the SPIRIVA capsule Do not breathe out into your HandiHaler device Keep your HandiHaler device in a horizontal position and keep your head upright looking straight ahead when breathing in Check the center chamber of your HandiHaler device f
43. tion Instruct patients that SPIRIVA HandiHaler is a once daily maintenance bronchodilator and should not be used for immediate relief of breathing problems i e as a rescue medication Distributed by Boehringer Ingelheim Pharmaceuticals Inc Ridgefield CT 06877 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 International GmbH Copyright 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED IT1600AED292014 10004551 12 IT5300H 75740 08 Patient Information SPIRIVA speh REE vah HandiHaler tiotropium bromide inhalation powder Do NOT swallow SPIRIVA capsules Important Information Do not swallow SPIRIVA capsules SPIRIVA capsules should only be used with the HandiHaler device and inhaled through your 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 e SPIRIVA HandiHaler is a prescription medicine used each day a maintenance medicine to control symptoms of chronic obstructive pulmonary disease COPD including chronic bronchiti
44. tions including short acting and long acting beta agonists inhaled and systemic steroids and theophyllines other than inhaled anticholinergics The patients were 40 to 88 years of age 75 male and 90 Caucasian with a diagnosis of COPD and a mean pre bronchodilator FEV of 39 predicted range 9 to 76 at study entry There was no difference between the groups in either of the co primary efficacy endpoints yearly rate of decline in pre and post bronchodilator FEV as demonstrated by similar slopes of FEV decline over time Figure 3 SPIRIVA HandiHaler maintained improvements in trough pre dose FEV adjusted means over 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 1 30 4 Tiotropium n 2494 Control n 2363 FEV L 01 6 12 18 24 30 36 42 48 een sta Month Repeated measure ANOVA was used to estimate means Means are adjusted for baseline measure ments Baseline trough FEV observed mean 1 12 Patients with gt 3 acceptable pulmonary function tests after Day 30 and non missing baseline value were included in the analysis Exacerbations The effect of SPIRIVA HandiHaler on COPD exacerbations was evaluated in two clinical trials a 4 year Clinical trial described above and a 6 month clinical trial of 1829 COPD patients in a Veterans Affairs setting In the 6 month trial COPD exacerbations were defined as a com
45. ultiples may be over estimated due to difficulties in measuring deposited doses in animal inhalation studies 11 DESCRIPTION SPIRIVA HandiHaler consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device Each light green hard gelatin SPIRIVA capsule contains 18 mcg tiotropium equivalent to 22 5 mcg tiotropium bromide monohydrate blended with lactose monohydrate which may contain milk proteins as the carrier The dry powder formulation within the SPIRIVA capsule is intended for oral inhalation only The active component of SPIRIVA HandiHaler is tiotropium The drug substance tiotropium bromide monohydrate is an anticholinergic with specificity for muscarinic receptors It is chemically described as 10 28 4B 5a 7B 7 Hydroxydi 2 thienylacetyl oxy 9 9 dimethyl 3 oxa 9 azoniatricyclo 3 3 1 02 nonane bromide monohydrate It is a synthetic non chiral quaternary ammonium compound Tiotropium bromide is a white or yellowish white powder It is sparingly soluble in water and soluble in methanol The structural formula is HCx CH N 9 Br H O Tiotropium bromide monohydrate has a molecular mass of 490 4 and a molecular formula of CioH22N0 4S Br H30 The HandiHaler device is an inhalation device used to inhale the dry powder contained in the SPIRIVA capsule The dry powder is delivered from the HandiHaler device at flow rates as low a
46. urinary excretion was 14 of the dose the remainder being mainly non absorbed drug in the gut which was eliminated via the feces The renal clearance of tiotropium exceeds the creatinine clearance indicating active secretion into the urine After chronic once daily inhalation by COPD patients pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter Drug Interactions An interaction study with tiotropium 14 4 mcg intravenous infusion over 15 minutes and cimetidine 400 mg three times daily or ranitidine 300 mg once daily was conducted Concomitant administration of cimetidine with tiotropium resulted in a 20 increase in the AUCo 4 a 28 decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours Co administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium Specific Populations Geriatric Patients As expected for drugs predominantly excreted renally advanced age was associated with a decrease of tiotropium renal clearance 326 mL min in COPD patients lt 58 years to 163 mL min in COPD patients gt 70 years which may be explained by decreased renal function Tiotropium excretion in urine after inhalation decreased from 14 young healthy volunteers to about 7 COPD patients Plasma concentrations were numerically increased with advancing age within COPD patients 43 increase in AUC after dry powder in
47. varying conditions adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice 6 Month to 1 Year Trials The data described below reflect exposure to SPIRIVA HandiHaler in 2663 patients SPIRIVA HandiHaler was studied in two 1 year placebo controlled trials two 1 year active controlled trials and two 6 month placebo controlled trials in patients with COPD In these trials 1308 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day The population had an age ranging from 39 to 87 years with 65 to 85 males 95 Caucasian and had COPD with a mean pre bronchodilator forced expiratory volume in one second FEV percent predicted of 39 to 43 Patients with narrow angle glaucoma or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials An additional 6 month trial conducted in a Veteran s Affairs setting is not included in this safety database because only serious adverse events were collected The most commonly reported adverse drug reaction was dry mouth Dry mouth was usually mild and often resolved during continued treatment Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation tachycardia blurred vision glaucoma new onset or worsening dysuria and urinary retentio
48. xicology and Pharmacology Reproductive Toxicology Studies No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium doses of up to 1 471 and 0 007 mg kg day respectively These doses correspond to approximately 660 and 6 times the RHDID on a mg m basis respectively However in rats fetal resorption litter loss decreases in the number of live pups at birth and the mean pup weights and a delay in pup sexual maturation were observed at inhalation tiotropium doses of 20 078 mg kg approximately 35 times the RHDID on a mg m basis In rabbits an increase in post implantation loss was observed at an inhalation dose of 0 4 mg kg day approximately 360 times the RHDID on a mg m basis Such effects were not observed at inhalation doses of 0 009 and up to 0 088 mg kg day in rats and rabbits respectively These doses correspond to approximately 4 and 80 times the RHDID on a mg m basis respectively These dose multiples may be over estimated due to difficulties in measuring deposited doses in animal inhalation studies 14 CLINICAL STUDIES The SPIRIVA HandiHaler clinical development program consisted of six Phase 3 studies in 2663 patients with COPD 1308 receiving SPIRIVA HandiHaler two 1 year placebo controlled studies two 6 month placebo controlled studies and two 1 year ipratropium controlled studies These studies enrolled patients who had a clinical diagnosis of COPD were 40 years of age or olde

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