Triohale

Ciclesonide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Triohale (Ciclesonide) reviews

1 INDICATIONS AND USAGE

Triohale Nasal Aerosol is a corticosteroid indicated for treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older. (1.1)

1.1 Treatment of Allergic Rhinitis

Triohale (Ciclesonide)^® (ciclesonide) Nasal Aerosol is indicated for the treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

For Intranasal use only

• 1 actuation per nostril once daily. (2.1)

2.1 Administration Information

Administer Triohale (Ciclesonide) by the intranasal route only. Prior to initial use, Triohale (Ciclesonide) must be primed by actuating three times. If Triohale (Ciclesonide) is not used for ten consecutive days, it must be primed by actuating three times. If Triohale (Ciclesonide) is dropped, the canister and actuator may become separated. If this happens, reassemble Triohale (Ciclesonide) and test spray once into the air before using. Illustrated patient's instructions for proper use accompany each package of Triohale (Ciclesonide).

2.2 Allergic Rhinitis

Adults and Adolescents (12 Years of Age and Older): The recommended dose of Triohale (Ciclesonide) is 1 actuation per nostril once daily (37 mcg per actuation). The maximum total daily dosage should not exceed 1 actuation in each nostril (74 mcg per day).

3 DOSAGE FORMS AND STRENGTHS

Triohale (Ciclesonide) Nasal Aerosol is provided at strength of 37 mcg per actuation strength containing 60 actuations per canister.

• Nasal Aerosol: 37 mcg of Triohale (Ciclesonide) per actuation. (3)
• Supplied in a 6.1 g canister containing 60 actuations. (16)

4 CONTRAINDICATIONS

Triohale (Ciclesonide) is contraindicated in patients with a known hypersensitivity to Triohale (Ciclesonide) or any of the ingredients of Triohale (Ciclesonide) [see Warnings and Precautions (5.3)].

• Patients with a known hypersensitivity to Triohale (Ciclesonide) or any of the ingredients of Triohale (Ciclesonide). (4)

5 WARNINGS AND PRECAUTIONS

• Local Nasal Effects, including epistaxis, ulceration, nasal septal perforations, Candida albicans infection impaired wound healing: Prior to initiating therapy, examine patients for evidence of septal perforation, erosions, ulceration, nasal surgery, and trauma. Avoid spraying Triohale directly onto the nasal septum. Avoid use in patients with recent septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal trauma. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue Triohale (Ciclesonide) if erosions, ulcerations or perforations occur. (5.1)
• Development of glaucoma or cataracts: Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, or cataracts. (5.2)
• Hypersensitivity reactions have been reported following administration of Triohale (Ciclesonide) with manifestations such as angioedema, with swelling of the lips, tongue and pharynx. (5.3)
• Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chicken pox or measles in susceptible individuals. Use caution in patients with the above because of the potential for worsening of these infections. (5.4)
• Hypercorticism and adrenal suppression: May occur with higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, discontinue Triohale (Ciclesonide) slowly. (5.5)
• Potential reduction in growth velocity in children: Monitor growth routinely in pediatric patients receiving Triohale (Ciclesonide). (5.6, 8.4)

5.1 Local Nasal Effects

Epistaxis and Nasal Ulceration: In clinical trials of 2 to 26 weeks in duration, epistaxis was observed more frequently in patients treated with Triohale (Ciclesonide) than those who received placebo. In the 26-week open-label extension of the perennial allergic rhinitis trial, nasal ulceration was identified in 4 of 824 patients administered Triohale (Ciclesonide) (148 mcg). [see Adverse Reactions (6)]

The occurrence of local nasal adverse events was further evaluated in a separate, postmarketing 26-week randomized, open-label, active-controlled nasal and ocular safety trial conducted in patients with perennial allergic rhinitis. In this study epistaxis was observed in 6% of patients treated with Triohale (Ciclesonide) and nasal ulceration was identified in 3 of 367 patients administered Triohale (Ciclesonide). [see Adverse Reactions (6)]

Nasal Septal Perforation: Nasal septal perforation has been reported in patients following the intranasal application of Triohale (Ciclesonide). Three short-term placebo-controlled trials (2 weeks) and one long-term (26 weeks with placebo control and 26 weeks open-label extension without placebo control) trial were conducted in patients with seasonal and perennial allergic rhinitis. Nasal septal perforations were reported in 2 patients out of 2335 treated with Triohale (Ciclesonide) compared with none of 892 treated with placebo. No nasal septal perforations were reported in 367 patients treated with Triohale (Ciclesonide) in a postmarketing 26-week, open-label, active-controlled trial in patients with perennial allergic rhinitis. [see Adverse Reactions (6)]

Before starting Triohale (Ciclesonide) conduct a nasal examination to ensure that patients are free of nasal disease other than allergic rhinitis. Periodically monitor patients with nasal examinations during treatment for adverse effects in the nasal cavity. If an adverse reaction (e.g. erosion, ulceration, perforation) is noted, discontinue Triohale (Ciclesonide). Avoid spraying Triohale (Ciclesonide) directly onto the nasal septum.

Candida Infection: In clinical trials with another formulation of Triohale (Ciclesonide), the development of localized infections of the nose or pharynx with Candida albicans has occurred. If such an infection develops with Triohale (Ciclesonide), it may require treatment with appropriate local therapy and discontinuation of Triohale (Ciclesonide).

Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use Triohale (Ciclesonide) until healing has occurred.

5.2 Glaucoma and Cataracts

Nasal and inhaled corticosteroids may result in the development of glaucoma and cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, or cataracts.

5.3 Hypersensitivity

Triohale is contraindicated in patients with a known hypersensitivity to Triohale (Ciclesonide) or any of the ingredients of Triohale (Ciclesonide). Cases of hypersensitivity reactions following administration of Triohale (Ciclesonide) with manifestations such as angioedema, with swelling of the lips, tongue and pharynx, have been reported.

5.4 Immunosuppression

Patients who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; or in patients with untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex because of the potential for worsening of these infections.

5.5 Hypothalamic-Pituitary-Adrenal Axis Suppression

Hypercorticism and adrenal suppression may occur when intranasal corticosteroids, such as Triohale, are used at higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, the dosage of Triohale (Ciclesonide) should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.

5.6 Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely (e.g., via stadiometry) in pediatric patients receiving Triohale (Ciclesonide). [see Pediatric Use (8.4)]

6 ADVERSE REACTIONS

Systemic and local corticosteroid use may result in the following:

• Epistaxis, ulcerations, nasal septal perforations, Candida albicans infection, impaired wound healing [see Warnings and Precautions ]
• Glaucoma and cataracts [see Warnings and Precautions (5.2)]
• Immunosuppression [see Warnings and Precautions (5.4)]
• Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.4)]

The most common adverse reactions (≥2% incidence) included nasal discomfort, headache and epistaxis. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

The safety data described below for adults and adolescents 12 years of age and older are based on 4 clinical trials evaluating doses of Triohale (Ciclesonide) nasal aerosol from 74 to 282 mcg. Three of the clinical trials were 2 to 6 weeks in duration and one trial was 26 weeks in duration with an additional 26-week open-label extension. Data from the first 6 weeks of the 26-week trial were pooled with data from the three 2-week trials. Short-term data (2 to 6 weeks) included 3001 patients with seasonal and perennial allergic rhinitis, of these, 884 received ZETONNA 74 mcg once daily and 892 received placebo. The short-term data included 1098 (36.6%) males, 1903 (63.4%) females, 2587 (86.2%) Caucasians, 320 (10.7%) Blacks, 49 (1.6%) Asians, and 45 (1.5%) patients classified as Other. The 26-week trial was conducted in 1110 patients with perennial allergic rhinitis [394 (35.5%) males and 716 (64.5%) females, ages 12 to 78 years old] treated with Triohale (Ciclesonide) 74 mcg, 148 mcg or placebo once daily. Of these patients, 298 were treated with 74 mcg Triohale (Ciclesonide), 505 with 148 mcg, and 307 with placebo. The racial distribution in this trial included 922 (83.1%) Caucasians, 146 (13.2%) Blacks, 18 (1.6%) Asians, and 24 (2.2%) patients classified as Other. The 26-week open-label extension included 824 patients [295 (35.8%) males and 529 (64.2%) females, ages 12 to 79 years old] given Triohale (Ciclesonide) 148 mcg once daily. The racial distribution in the open-label extension included 690 (83.7%) Caucasians, 104 (12.6%) Blacks, 15 (1.8%) Asians, and 15 (1.8%) patients classified as Other.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.

Short-Term (2-6 weeks) Trials:

In three short-term trials and the first 6 weeks of one long-term trial, conducted in the US, 884 patients with a history of seasonal or perennial allergic rhinitis were treated with Triohale (Ciclesonide) 74 mcg daily. Adverse reactions did not differ appreciably based on age, gender, or race. The table below displays reactions that occurred with an incidence of at least 2.0% and more frequently with Triohale (Ciclesonide) 74 mcg than with placebo in seasonal or perennial allergic rhinitis clinical trials of 2 to 6 weeks duration.

a Nasal discomfort includes both nasal discomfort and instillation site discomfort
Adverse Reaction	Triohale (Ciclesonide) Nasal Aerosol 74 mcg Once Daily N = 884	Placebo N = 892
Nasal discomforta	28 (3.2%)	16 (1.8%)
Headache	27 (3.1%)	11 (1.2%)
Epistaxis	26 (2.9%)	24 (2.7%)

When considering the data from higher doses evaluated in the short-term trials, epistaxis demonstrated a dose response. In addition, two patients treated with Triohale (Ciclesonide) 74 mcg experienced nasal septal perforations in the short-term trials compared to no patients treated with placebo.

Approximately 1.2% of patients treated with Triohale (Ciclesonide) 74 mcg in clinical trials discontinued because of adverse reactions; this rate was similar for patients treated with placebo. Discontinuations due to local adverse reactions were similar in Triohale (Ciclesonide) 74 mcg treated patients (0.8%) compared to placebo treated patients (0.8%). Local adverse reactions leading to discontinuation that occurred only in Triohale (Ciclesonide) treated patients included ear infection, nasal discomfort, nasal dryness, nasal mucosal/septum disorders, pharyngitis, streptococcal pharyngitis, sinus headache, and tonsillitis.

Long-Term (26-Week Double-Blind and 26-Week Open-Label) Safety Trial:

In one 26-week double-blind, placebo-controlled safety trial that included 1110 adult and adolescent patients with perennial allergic rhinitis, additional adverse reactions, with an incidence of at least 2%, that occurred more frequently with Triohale (Ciclesonide) than with placebo were upper respiratory tract infection, urinary tract infection, oropharyngeal pain, nasal mucosal/septum disorders, viral upper respiratory tract infection, cough, influenza, bronchitis, streptococcal pharyngitis, muscle strain, and nausea. Nasal discomfort (5.7%) and epistaxis

(11.4%) were also more frequent in the 26-week safety trial compared to clinical trials 2 to 6 weeks in duration. Nasal mucosal/septum disorders and cough demonstrated a dose response.

Discontinuations due to adverse reactions were higher in Triohale (Ciclesonide) treated patients compared to placebo treated patients and demonstrated a dose response. Local adverse reactions leading to discontinuation were also higher in Triohale (Ciclesonide) 74 mcg treated patients (1.7%) compared to placebo treated patients (0.7%). The only local adverse reaction leading to discontinuation that occurred in Triohale (Ciclesonide) treated patients and was not observed in the 2- to 6-week trials was upper respiratory tract infection.

A total of 824 patients with perennial allergic rhinitis who completed the 26-week double-blind trial enrolled into an open-label extension and received Triohale (Ciclesonide) 148 mcg for 26 weeks. Additional adverse reactions, observed with an incidence of at least 2% were sinusitis, nasopharyngitis, and back pain.

A total of 4 nasal septal ulcerations were also reported in the 26-week open-label extension.

There were no reports of nasal septal perforations in the long-term safety trial.

Long-Term (6-Month Open-Label) Nasal Safety Trial:

Nasal and ocular safety was evaluated in one 26-week, postmarketing, randomized, open-label, active-controlled trial, in adult and adolescent patients 12-74 years of age with a history of perennial allergic rhinitis. A total of 737 patients were treated with Triohale (Ciclesonide) 74 mcg or Triohale (Ciclesonide) nasal spray 200 mcg once daily. The combined incidence of nasal mucosal or septum disorders, including erosions and ulcerations, was 3 (0.8%) for Triohale (Ciclesonide) 74 mcg and 4 (1.1%) for Triohale (Ciclesonide) nasal spray 200 mcg treated patients. There were no nasal septal perforations reported with either treatment. Ocular findings, including the development or worsening of lens opacities, increase in intraocular pressure, and worsening visual acuity, were also evaluated over the 26-week treatment period. The occurrence of ocular safety events was similar for the Triohale (Ciclesonide) 74 mcg and Triohale (Ciclesonide) nasal spray 200 mcg treatment groups.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of other formulations of Triohale (Ciclesonide), ALVESCO^® Inhalation Aerosol and OMNARIS^® Nasal Spray. 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.

ALVESCO^® Inhalation Aerosol: immediate or delayed hypersensitivity reactions such as angioedema with swelling of the lips, tongue, and pharynx.

OMNARIS^® Nasal Spray: nasal congestion, nasal ulcer, and dizziness. Localized infections of the nose or mouth with Candida albicans have also occurred with OMNARIS^® Nasal Spray.

7 DRUG INTERACTIONS

In vitro studies and clinical pharmacology studies suggested that des-ciclesonide has no potential for metabolic drug interactions or protein binding-based drug interactions [see Clinical Pharmacology (12.3)]. In a drug interaction study, co-administration of orally inhaled Triohale (Ciclesonide) and oral ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels of Triohale (Ciclesonide) remained unchanged. Erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin following oral inhalation of Triohale (Ciclesonide) [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 trials in pregnant women. Triohale should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Oral administration of Triohale (Ciclesonide) in rats at approximately 120 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mcg/m² basis at a maternal dose of 900 mcg/kg/day) produced no teratogenicity or other fetal effects. However, subcutaneous administration of Triohale (Ciclesonide) in rabbits at similar to MRHDID (on a mcg/m² basis at a maternal dose of 5 mcg/kg/day) produced fetal toxicity. This included fetal loss, reduced fetal weight, cleft palate, skeletal abnormalities including incomplete ossifications, and skin effects. No toxicity was observed at ¼ of the MRHDID in adults (on a mcg/m² basis at a maternal dose of 1 mcg/kg/day).

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.3 Nursing Mothers

It is not known if Triohale (Ciclesonide) is excreted in human milk. However, other corticosteroids are excreted in human milk. In a study with lactating rats, minimal but detectable levels of radiolabeled Triohale (Ciclesonide) were recovered in milk. Caution should be used when Triohale (Ciclesonide) is administered to nursing women.

8.4 Pediatric Use

The safety and effectiveness for seasonal and perennial allergic rhinitis in children 12 years of age and older have been established. The safety and efficacy of Triohale for treatment of the symptoms of seasonal and perennial allergic rhinitis in patients 11 years of age and younger have not been established.

The safety and efficacy of Triohale (Ciclesonide) in pediatric patients 6-11 years of age were evaluated in two randomized, double blind, parallel placebo-controlled clinical trials in 1693 pediatric patients with allergic rhinitis. Of the two trials, one was 2 weeks in duration and evaluated the efficacy of two doses of Triohale (Ciclesonide) (37 mcg and 74 mcg once daily) in 847 patients with seasonal allergic rhinitis. The second clinical trial was 12 weeks in duration and evaluated the efficacy of two doses of Triohale (Ciclesonide) (37 mcg and 74 mcg once daily) in 846 patients with perennial allergic rhinitis. The trials were similar in design to the trials conducted in adolescents and adults. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average morning and evening reflective total nasal symptom scores (rTNSS) averaged over 2 weeks of treatment in the seasonal allergic rhinitis trial and over the first 6 weeks of treatment in the perennial allergic rhinitis trial. In the 2-week trial in patients with seasonal allergic rhinitis, treatment with Triohale (Ciclesonide) at either dose failed to demonstrate efficacy. In the 12-week trial in patients with perennial allergic rhinitis, Triohale (Ciclesonide) 37 mcg and 74 mcg once daily both demonstrated significant improvement in rTNSS compared to placebo with treatment differences of 0.59 (95% CI: 0.23, 0.95) and 0.47 (95% CI: 0.11, 0.83), respectively. The safety profile observed in children 6 to 11 years of age with seasonal or perennial allergic rhinitis was similar to the adverse reactions observed in the clinical trial population of patients 12 year of age and older [see Adverse Reactions (6.1)].

The effect of Triohale (Ciclesonide) on the HPA axis was evaluated in one placebo-controlled clinical study of 6 weeks in duration in children 6 to11 years of age with perennial allergic rhinitis [see Clinical Pharmacology (12.2)].

Studies in children under 6 years of age have not been conducted.

Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Triohale (Ciclesonide), should be monitored routinely (e.g., via stadiometry). A 52-week, multi-center, double-blind, randomized, placebo-controlled parallel-group trial was conducted to assess the effect of orally inhaled Triohale (Ciclesonide) (ALVESCO^® Inhalation Aerosol) on growth rate in 609 pediatric patients with mild persistent asthma, aged 5 to 8.5 years. Treatment groups included orally inhaled Triohale (Ciclesonide) 40 mcg or 160 mcg or placebo given once daily. Growth was measured by stadiometer height during the baseline, treatment and follow-up periods. The primary comparison was the difference in growth rates between Triohale (Ciclesonide) 40 and 160 mcg and placebo groups. Conclusions cannot be drawn from this trial because compliance could not be assured. Triohale (Ciclesonide) blood levels were also not measured during the one-year treatment period. There was no difference in efficacy measures between the placebo and the orally inhaled Triohale (Ciclesonide) (ALVESCO^® Inhalation Aerosol) groups.

The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

The potential for Triohale (Ciclesonide) to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

8.5 Geriatric Use

Clinical trials of Triohale (Ciclesonide) did not include sufficient numbers of patients age 65 and over to determine whether they responded differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Chronic overdosage may result in signs or symptoms of hypercorticism [see Warnings and Precautions (5.5)]. There are no data on the effects of acute or chronic overdosage with Triohale (Ciclesonide).

11 DESCRIPTION

The active component of Triohale (Ciclesonide) is Triohale (Ciclesonide), a non-halogenated glucocorticoid having the chemical name pregna -1,4-diene-3,20-dione, 16,17-[[R-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-,(11ß,16α)-. Triohale (Ciclesonide) is delivered as the R-epimer. The empirical formula is C₃₂H₄₄O₇ and its molecular weight is 540.7. Its structural formula is as follows:

Priming Your Triohale (Ciclesonide) Nasal Aerosol For Use

• Remove Triohale (Ciclesonide) Nasal Aerosol from its package.
• Before you use Triohale (Ciclesonide) Nasal Aerosol for the first time or if you have not used your medicine for 10 days in a row, you will need to prime your Triohale (Ciclesonide) Nasal Aerosol.
• Open the purple plastic dust cap by gently squeezing both sides and pulling the cap away from the nasal actuator. Hold the nasal actuator upright. (See Figure B )

• Spray 3 times into the air away from the face, by pressing down fully on the top of the canister three times (See Figure C ). Make sure the canister returns to its original position after each spray.

Using Your Triohale (Ciclesonide) Nasal Aerosol

Step 1. Open the purple plastic dust cap.

Step 2. Hold the nasal actuator upright, with the nose piece pointing upwards, between your thumb and forefinger (and middle finger) (See Figure D ).

Step 3. Tilt your head back slightly and insert the end of the nose piece into 1 nostril, pointing it slightly toward the outside nostril wall away from the nasal septum (the wall between the 2 nostrils), while holding your other nostril closed with 1 finger (See Figure E ). Do not get any spray in your eyes or directly on your nasal septum.

Step 4. Press down on the canister to release 1 spray and at the same time breathe in gently through the nostril. Hold your breath for a few seconds then breathe out slowly through your mouth.

Step 5. Remove the nose piece from your nostril. Make sure the canister has returned to its original position and repeat steps 2-4 for the second spray in your other nostril.

Step 6. Replace the protective purple dust cap on the nasal actuator.

Step 7. Avoid blowing your nose for the next 15 minutes.

Cleaning Your Nasal Actuator

The outside of the nose piece should be cleaned weekly, by wiping with a clean, dry tissue or cloth (see Figure F ).

Do not wash or put any part of the Triohale (Ciclesonide) Nasal Aerosol canister or actuator in water.

How to Tell if Your Triohale (Ciclesonide) Nasal Aerosol Is Empty

• Each canister of Triohale (Ciclesonide) Nasal Aerosol contains enough medicine for you to spray medicine 60 times (or 30 times for sample size product). This does not count the first 3 priming sprays.
• The actuator of your Triohale (Ciclesonide) Nasal Aerosol is fitted with a dose indicator which shows you how much medicine is left after each use. The dose indicator will display the number of sprays remaining in groups of 5 or 10 actuations.
• The display window will begin showing a green color. As you continue to use the medicine, the window will show a yellow color. A yellow color in the window means that you need to replace your medicine soon. When the medicine is almost empty, the window will show a red color.
• When the window shows red and you see the dose indicator read zero, “0” (see Figure G ), you should throw away the canister and nasal actuator.

• Do not throw your Triohale (Ciclesonide) Nasal Aerosol canister in the fire or an incinerator.
• Do not use your Triohale (Ciclesonide) Nasal Aerosol after zero is shown in the window of the dose indicator even though it may look like there is medicine left in the canister. You may not get the right amount of medicine.
• Talk with your healthcare provider before your supply of Triohale (Ciclesonide) Nasal Aerosol runs out to see if you should get a refill of your medicine.

What to Do if You Drop Your Triohale (Ciclesonide) Nasal Aerosol

• If you drop your Triohale (Ciclesonide) Nasal Aerosol, the canister may become separated from the actuator. If this happens, insert the canister into the actuator as shown in Figure H , test spray once into the air away from your face, then use as described above.

• If the Triohale (Ciclesonide) Nasal Aerosol is dropped, the dose counter may not work. It is recommended to keep track of the number of sprays taken from your Triohale (Ciclesonide) Nasal Aerosol based on your records.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

SUNOVION

Manufactured for:

Sunovion Pharmaceuticals Inc.

Marlborough, MA 01752 USA

Made in the United Kingdom

© 2014 Sunovion Pharmaceuticals Inc. All rights reserved.

For customer service, call 1-888-394-7377

901641R01

620392213

Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - carton – 37 mcg 60-count

NDC 63402-737-60

Net Contents: 6.1 g

Triohale (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Triohale (Ciclesonide) Nasal Aerosol Canister

Should Be Used with Triohale (Ciclesonide)

Nasal Aerosol Actuator Only.

60 Metered Actuations

Rx ONLY

Sunovion

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – canister - 37 mcg 60-count

NDC 63402-737-60

Net Contents: 6.1 g

Triohale (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Use with Triohale (Ciclesonide) Nasal Aerosol

Actuator Only.

60 Metered Actuations

Rx ONLY

Sunovion

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – actuator - 37 mcg 60-count

Triohale (Ciclesonide)

(ciclesonide) Nasal Aerosol

37 mcg per actuation

For Intranasal Use Only.

Use with Triohale (Ciclesonide)

Nasal Aerosol Canister Only.

60 Metered Actuations

Formoterol Fumarate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• How supplied/storage and handling
• Patient counseling information
• Medication guide
• Triohale (Formoterol Fumarate) reviews

WARNING: ASTHMA-RELATED DEATH

Long-acting beta₂-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta₂-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in Triohale (Formoterol Fumarate) Inhalation Solution. The safety and efficacy of Triohale (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Triohale (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication .

WARNING: ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning.

• Long-acting beta₂-adrenergic agonists (LABA) increase the risk of asthma-related death. (5.1)
• A placebo-controlled study with another long-acting beta₂-adrenergic agonist (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. (5.1)
• The finding of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in Triohale (Formoterol Fumarate). The safety and efficacy of Triohale (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Triohale (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. (4, 5.1)

1 INDICATIONS AND USAGE

Triohale Inhalation Solution is a long-acting beta₂-adrenergic agonist (beta₂-agonist) indicated for:

• Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. (1.1)

Important limitations of use:

• Triohale (Formoterol Fumarate) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. (1.2, 5.2)
• Triohale (Formoterol Fumarate) Inhalation Solution is not indicated to treat asthma. (1.2)

1.1 Maintenance Treatment of COPD

Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

1.2 Important Limitations of Use

Triohale (Formoterol Fumarate) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease .

Triohale (Formoterol Fumarate) Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of Triohale (Formoterol Fumarate) Inhalation Solution in asthma have not been established.

2 DOSAGE AND ADMINISTRATION

The recommended dose of Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose greater than 40 mcg is not recommended.

Triohale (Formoterol Fumarate) Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor. The safety and efficacy of Triohale (Formoterol Fumarate) Inhalation Solution have been established in clinical trials when administered using the PARI-LC Plus^® nebulizer (with a facemask or mouthpiece) and the PRONEB^® Ultra compressor. The safety and efficacy of Triohale (Formoterol Fumarate) Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

Triohale (Formoterol Fumarate) Inhalation Solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE. Contents of any partially used container should be discarded.

If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.

The drug compatibility (physical and chemical), efficacy, and safety of Triohale (Formoterol Fumarate) Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

For oral inhalation only.

• One 20 mcg/2 mL vial every 12 hours (2)
• For use with a standard jet nebulizer (with a facemask or mouthpiece) connected to an air compressor (2)

3 DOSAGE FORMS AND STRENGTHS

Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as a sterile solution for nebulization in low-density polyethylene unit-dose vials. Each vial contains Triohale (Formoterol Fumarate) dihydrate, USP equivalent to 20 mcg/2 mL of Triohale (Formoterol Fumarate).

Inhalation Solution (unit dose vial for nebulization); 20 mcg/2 mL solution (3)

4 CONTRAINDICATIONS

All LABA, including Triohale (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. .

• All LABA, including Triohale (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. (4)

5 WARNINGS AND PRECAUTIONS

• Do not initiate Triohale Inhalation Solution in acutely deteriorating patients. (5.2)
• Do not use for relief of acute symptoms. Concomitant short-acting beta₂-agonists can be used as needed for acute relief. (5.2)
• Do not exceed the recommended dose. Excessive use of Triohale (Formoterol Fumarate) Inhalation Solution, or use in conjunction with other medications containing long-acting beta₂-agonists, can result in clinically significant cardiovascular effects, and may be fatal. (5.3, 5.5)
• Life-threatening paradoxical bronchospasm can occur. Discontinue Triohale (Formoterol Fumarate) Inhalation Solution immediately. (5.4)
• Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or with sensitivity to sympathomimetic drugs. (5.6, 5.7)

5.1 Asthma-Related Deaths

Data from a large placebo-controlled study in asthma patients showed that long-acting beta₂-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta₂-adrenergic agonists.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta₂-adrenergic agonists, including Triohale (Formoterol Fumarate) Inhalation Solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with Triohale (Formoterol Fumarate) Inhalation Solution has been conducted. The safety and efficacy of Triohale (Formoterol Fumarate) in patients with asthma have not been established. All LABA, including Triohale (Formoterol Fumarate), are contraindicated in patients with asthma without use of a long-term asthma control medication. .

Clinical studies with Triohale (Formoterol Fumarate) administered as a dry powder inhaler suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.

5.2 Deterioration of Disease and Acute Episodes

Triohale Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Triohale (Formoterol Fumarate) Inhalation Solution has not been studied in patients with acutely deteriorating COPD. The use of Triohale (Formoterol Fumarate) Inhalation Solution in this setting is inappropriate.

Triohale (Formoterol Fumarate) Inhalation Solution should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Triohale (Formoterol Fumarate) Inhalation Solution has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta₂-agonist.

When beginning Triohale (Formoterol Fumarate) Inhalation Solution, patients who have been taking inhaled, short-acting beta₂-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing Triohale (Formoterol Fumarate) Inhalation Solution, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist and instruct the patient how it should be used. Increasing inhaled beta₂-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Triohale (Formoterol Fumarate) Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta₂-agonist becomes less effective or the patient needs more inhalation of short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of Triohale (Formoterol Fumarate) Inhalation Solution beyond the recommended 20 mcg twice daily dose is not appropriate in this situation.

5.3 Excessive Use and Use with Other Long-Acting Beta₂-Agonists

As with other inhaled beta₂-adrenergic drugs, Triohale (Formoterol Fumarate) Inhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.4 Paradoxical Bronchospasm

As with other inhaled beta₂-agonists, Triohale Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Triohale (Formoterol Fumarate) Inhalation Solution should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

Triohale (Formoterol Fumarate) Inhalation Solution, like other beta₂-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, Triohale (Formoterol Fumarate) Inhalation Solution may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Triohale (Formoterol Fumarate) Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.6 Coexisting Conditions

Triohale Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.7 Hypokalemia and Hyperglycemia

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects . The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients.

Clinically significant changes in serum potassium and blood glucose were infrequent during clinical studies with long-term administration of Triohale (Formoterol Fumarate) Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Triohale (Formoterol Fumarate) Inhalation Solution, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm.

6 ADVERSE REACTIONS

Long acting beta₂-adrenergic agonists such as formoterol increase the risk of asthma-related death .

Most common adverse reactions (>2% and more common than placebo) are diarrhea, nausea, nasopharyngitis, dry mouth, vomiting, dizziness, and insomnia (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Specialty L.P. at 1-800-429-7751 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Beta₂-Agonist Adverse Reaction Profile

Adverse reactions to Triohale (Formoterol Fumarate) Inhalation Solution are expected to be similar in nature to other beta₂-adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, muscle cramps, palpitations, nausea, dizziness, fatigue, malaise, insomnia, hypokalemia, hyperglycemia, and metabolic acidosis.

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely 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.

Adults with COPD

The data described below reflect exposure to Triohale Inhalation Solution 20 mcg twice daily by oral inhalation in 586 patients, including 232 exposed for 6 months and 155 exposed for at least 1 year. Triohale (Formoterol Fumarate) Inhalation Solution was studied in a 12-week, placebo- and active-controlled trial (123 subjects treated with Triohale (Formoterol Fumarate) Inhalation Solution) and a 52-week, active-controlled trial (463 subjects treated with Triohale (Formoterol Fumarate) Inhalation Solution). Patients were mostly Caucasians (88%) between 40-90 years old (mean, 64 years old) and had COPD, with a mean FEV₁ of 1.33 L. Patients with significant concurrent cardiac and other medical diseases were excluded from the trials.

Table 1 shows adverse reactions from the 12-week, double-blind, placebo-controlled trial where the frequency was greater than or equal to 2% in the Triohale (Formoterol Fumarate) Inhalation Solution group and where the rate in the Triohale (Formoterol Fumarate) Inhalation Solution group exceeded the rate in the placebo group. In this trial, the frequency of patients experiencing cardiovascular adverse events was 4.1% for Triohale (Formoterol Fumarate) Inhalation Solution and 4.4% for placebo. There were no frequently occurring specific cardiovascular adverse events for Triohale (Formoterol Fumarate) Inhalation Solution (frequency greater than or equal to 1% and greater than placebo). The rate of COPD exacerbations was 4.1% for Triohale (Formoterol Fumarate) Inhalation Solution and 7.9% for placebo.

Number of patients with adverse reactions in the 12-week multiple-dose controlled clinical trial
Adverse Reaction	Triohale (Formoterol Fumarate) Inhalation Solution 20 mcg		Placebo
	n	(%)	n	(%)
Total Patients	123	(100)	114	(100)
Diarrhea	6	(4.9)	4	(3.5)
Nausea	6	(4.9)	3	(2.6)
Nasopharyngitis	4	(3.3)	2	(1.8)
Dry Mouth	4	(3.3)	2	(1.8)
Vomiting	3	(2.4)	2	(1.8)
Dizziness	3	(2.4)	1	(0.9)
Insomnia	3	(2.4)	0	0

Patients treated with Triohale (Formoterol Fumarate) Inhalation Solution 20 mcg twice daily in the 52-week open-label trial did not experience an increase in specific clinically significant adverse events above the number expected based on the medical condition and age of the patients.

6.3 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Triohale (Formoterol Fumarate) Inhalation Solution. 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.

Anaphylactic reactions, urticaria, angioedema (presenting as face, lip, tongue, eye, pharyngeal, or mouth edema), rash, and bronchospasm

7 DRUG INTERACTIONS

• Other adrenergic drugs may potentiate effect. Use with caution.
• Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. (5.7, 7.2, 7.3)
• MAO inhibitors, tricyclic antidepressants and drugs that prolong QTc interval may potentiate effect on the cardiovascular system. Use with extreme caution. (7.4)
• Beta-blockers may decrease effectiveness. Use with caution and only when medically necessary. (7.5)

7.1 Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol may be potentiated .

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists .

7.3 Non-potassium Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.

7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

Formoterol, as with other beta₂-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.5 Beta-blockers

Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

Triohale administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. However, Triohale (Formoterol Fumarate) was found to be teratogenic in rats and rabbits in other testing laboratories. When given to rats throughout organogenesis, oral doses of 0.2 mg/kg (approximately 40 times the maximum recommended daily inhalation dose in humans on a mg/m² basis) and above delayed ossification of the fetus, and doses of 6 mg/kg (approximately 1200 times the maximum recommended daily inhalation dose in humans on a mg/m² basis) and above decreased fetal weight. Triohale (Formoterol Fumarate) has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg. Because there are no adequate and well-controlled studies in pregnant women, Triohale (Formoterol Fumarate) Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physician if they become pregnant while taking Triohale (Formoterol Fumarate) Inhalation Solution.

8.2 Labor and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of Triohale (Formoterol Fumarate) Inhalation Solution during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, Triohale (Formoterol Fumarate) Inhalation Solution should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers

In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if Triohale Inhalation Solution is administered to nursing women. There are no well-controlled human studies of the use of Triohale (Formoterol Fumarate) Inhalation Solution in nursing mothers.

Women should be advised to contact their physician if they are nursing while taking Triohale (Formoterol Fumarate) Inhalation Solution.

8.4 Pediatric Use

Triohale (Formoterol Fumarate) Inhalation Solution is not indicated for use in children. The safety and effectiveness of Triohale (Formoterol Fumarate) Inhalation Solution in pediatric patients have not been established. The pharmacokinetics of Triohale (Formoterol Fumarate) has not been studied in pediatric patients.

8.5 Geriatric Use

Of the 586 subjects who received Triohale (Formoterol Fumarate) Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received Triohale (Formoterol Fumarate) Inhalation Solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of Triohale (Formoterol Fumarate) Inhalation Solution has not been studied in elderly subjects.

10 OVERDOSAGE

The expected signs and symptoms with overdosage of Triohale (Formoterol Fumarate) Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS. Signs and symptoms may include angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of Triohale (Formoterol Fumarate) Inhalation Solution.

Treatment of overdosage consists of discontinuation of Triohale (Formoterol Fumarate) Inhalation Solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Triohale (Formoterol Fumarate) Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.

The minimum lethal inhalation dose of Triohale (Formoterol Fumarate) in rats is 156 mg/kg (approximately 32,000 times the maximum recommended daily inhalation dose in humans on a mg/m² basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the maximum recommended daily inhalation dose in humans.

For additional information about overdose treatment, call a poison control center (1-800-222-1222).

11 DESCRIPTION

Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as 2 mL of Triohale (Formoterol Fumarate) inhalation solution packaged in a 2.5 mL single-use low-density polyethylene vial and overwrapped in a foil pouch. Each vial contains 2 mL of a clear, colorless solution composed of Triohale (Formoterol Fumarate) dihydrate, USP equivalent to 20 mcg of Triohale (Formoterol Fumarate) in an isotonic, sterile aqueous solution containing sodium chloride, pH adjusted to 5.0 with citric acid and sodium citrate.

The active component of Triohale (Formoterol Fumarate) Inhalation Solution is Triohale (Formoterol Fumarate) dihydrate, USP, a racemate. Triohale (Formoterol Fumarate) dihydrate is a beta₂-adrenergic bronchodilator. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is:

Figure 2 Mean* FEV1 at Endpoint after 12 Weeks of Treatment

• * Figures show least-squares means adjusted for baseline FEV₁

Patients treated with Triohale (Formoterol Fumarate) Inhalation Solution used less rescue albuterol during the trial compared to patients treated with placebo.

Examination of age (≥ 65 or younger) and gender subgroups did not identify differences in response to Triohale (Formoterol Fumarate) Inhalation Solution. There were too few non-Caucasian subjects to assess differences in populations defined by race adequately.

In the 12 week study, 78% of subjects achieved a 15% increase from baseline FEV₁ following the first dose of Triohale (Formoterol Fumarate) Inhalation Solution 20 mcg. In these subjects, the median time to onset of bronchodilation, defined as 15% increase in FEV₁, was 11.7 minutes. When defined as an increase in FEV₁ of 12% and 200 mL, the time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak bronchodilator effect was 2 hours after dosing.

Triohale (Formoterol Fumarate) Figure 1 Triohale (Formoterol Fumarate) Figure 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution is supplied as a 2 mL sterile solution for nebulization in 2.5 mL low-density polyethylene unit dose vials. Each vial is overwrapped in a foil pouch and supplied in cartons as listed below.

Carton of 30 individually wrapped unit dose vials, NDC 49502-605-30

Carton of 60 individually wrapped unit dose vials, NDC 49502-605-61

Storage and Handling:

Prior to dispensing to the patient: Store in a refrigerator, 2°C to 8°C (36°F to 46°F)

After dispensing to the patient: Store at 2°C to 25°C (36°F to 77°F) for up to 3 months. Protect pouch from heat.

• Triohale (Formoterol Fumarate) Inhalation Solution should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow and equipped with a facemask or mouthpiece.
• Vial should always be stored in the foil pouch, and only removed IMMEDIATELY before use.
• Do not take by mouth.
• Contents of any partially used container should be discarded.
• Discard the container and top after use.
• Keep out of the reach of children

17 PATIENT COUNSELING INFORMATION

Asthma-Related Death

Patients should be informed that long acting beta agonist, such as Triohale (Formoterol Fumarate), increase the risk of asthma-related death. All LABA, including Triohale (Formoterol Fumarate), should not be used in patients with asthma without use of a long-term asthma control medication.

Acute Exacerbations or Deteriorations

Triohale (Formoterol Fumarate) Inhalation Solution is not indicated for relief of acute symptoms, and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist (the healthcare provider should provide the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen despite recommended doses of Triohale (Formoterol Fumarate) Inhalation Solution, if Triohale (Formoterol Fumarate) Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta₂-agonist than usual.

Appropriate Dosing

Patients should not stop using Triohale (Formoterol Fumarate) Inhalation Solution unless told to do so by a healthcare provider because symptoms may get worse. Patients should not inhale more than the prescribed number of vials at any one time. The daily dosage of Triohale (Formoterol Fumarate) Inhalation Solution should not exceed one vial twice daily (40 mcg total daily dose). Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

Concomitant Therapy

Patients who have been taking inhaled, short-acting beta₂-agonists (e.g., albuterol) on a regular basis should be instructed to discontinue the regular use of these products and use them only for symptomatic relief of acute symptoms. Triohale (Formoterol Fumarate) Inhalation Solution should not be used in conjunction with other inhaled medications containing long-acting beta₂-agonists. Patients should be warned not to stop or change the dose of other concomitant COPD therapy without medical advice, even if symptoms improve after initiating treatment with Triohale (Formoterol Fumarate) Inhalation Solution.

Common Adverse Reactions with Beta₂-agonists

Patients should be informed that treatment with beta₂-agonists may lead to adverse reactions that include palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor, nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar, high blood acid, or trouble sleeping .

Instructions for Administration

It is important that patients understand how to use Triohale (Formoterol Fumarate) Inhalation Solution with a nebulizer appropriately . Patients should be instructed not to mix other medications with Triohale (Formoterol Fumarate) Inhalation Solution or ingest Triohale (Formoterol Fumarate) Inhalation Solution. Patients should throw the plastic dispensing container away immediately after use. Due to their small size, the container and top pose a danger of choking to young children.

FDA-Approved Medication Guide

See the accompanying Medication Guide.

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

U.S. Pat. No. 6,667,344

U.S. Pat. No. 6,814,953

A3-031-00

MEDICATION GUIDE

Triohale (Formoterol Fumarate)^®(Per-FOR-o-mist)

(formoterol fumarate) Inhalation Solution

Triohale (Formoterol Fumarate) Inhalation Solution is only for use with a nebulizer.

Read the Medication Guide that comes with Triohale (Formoterol Fumarate) Inhalation Solution before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Triohale (Formoterol Fumarate) Inhalation Solution?

Triohale (Formoterol Fumarate) Inhalation Solution can cause serious side effects including:

• People with asthma who take long-acting beta₂ adrenergic agonist (LABA) medicines such as Triohale (Formoterol Fumarate) Inhalation Solution have an increased risk of death from asthma problems.
• It is not known if LABA medicines, such as Triohale (Formoterol Fumarate) Inhalation Solution, increase the risk of death in people with chronic obstructive pulmonary disease (COPD).
• Get emergency medical care if:
  • breathing problems worsen quickly
  • you use your rescue inhaler medicine, but it does not relieve your breathing problems

What is Triohale (Formoterol Fumarate) Inhalation Solution?

Triohale (Formoterol Fumarate) Inhalation Solution is used long term, 2 times a day (morning and evening), in controlling symptoms of chronic obstructive pulmonary disease (COPD) in adults with COPD.

Triohale (Formoterol Fumarate) Inhalation Solution is only for use with a nebulizer. LABA medicines such as Triohale (Formoterol Fumarate) Inhalation Solution help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath.

Triohale (Formoterol Fumarate) Inhalation Solution is not for use to treat sudden symptoms of COPD.

Triohale (Formoterol Fumarate) Inhalation Solution should not be used in children. It is not known if Triohale (Formoterol Fumarate) Inhalation Solution is safe and effective in children.

It is not known if Triohale (Formoterol Fumarate) Inhalation Solution is safe and effective in people with asthma.

Who should not use Triohale (Formoterol Fumarate) Inhalation Solution?

Do not use Triohale (Formoterol Fumarate) Inhalation Solution if you have asthma without using a long-term asthma control medicine.

What should I tell my healthcare provider before using Triohale (Formoterol Fumarate) Inhalation Solution?

Tell your healthcare provider about all of your health conditions, including if you:

• have heart problems
• have high blood pressure
• have diabetes
• have seizures
• have thyroid problems
• have liver problems
• are pregnant or planning to become pregnant. It is not known if Triohale (Formoterol Fumarate) Inhalation Solution can harm an unborn baby.
• are breastfeeding. It is not known if Triohale (Formoterol Fumarate) Inhalation Solution passes into breast milk and if it can harm your baby.

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Triohale (Formoterol Fumarate) Inhalation Solution and certain other medicines may interact with each other. This may cause serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use Triohale (Formoterol Fumarate) Inhalation Solution?

Read the step-by-step instructions for using Triohale (Formoterol Fumarate) Inhalation Solution at the end of this Medication Guide.

• Use Triohale (Formoterol Fumarate) Inhalation Solution exactly as prescribed. One ready-to-use vial of Triohale (Formoterol Fumarate) Inhalation Solution is one dose. The usual dose of Triohale (Formoterol Fumarate) Inhalation Solution is one ready-to-use vial, twice a day (morning and evening) breathed in through your nebulizer machine. The 2 doses should be about 12 hours apart. Do not use more than 2 vials of Triohale (Formoterol Fumarate) Inhalation Solution a day.
• Do not mix other medicines with Triohale (Formoterol Fumarate) Inhalation Solution in your nebulizer machine.
• If you miss a dose of Triohale (Formoterol Fumarate) Inhalation Solution, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at one time.
• While you are using Triohale (Formoterol Fumarate) Inhalation Solution 2 times each day:
  • do not use other medicines that contain a long-acting beta₂-agonist (LABA) for any reason.
  • do not use your short-acting beta₂-agonist medicine on a regular basis (four times a day).
• Triohale (Formoterol Fumarate) Inhalation Solution does not relieve sudden symptoms of COPD. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have one prescribed for you.
• Do not stop using Triohale (Formoterol Fumarate) Inhalation Solution or other medicines to control or treat your COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.
• Do not use Triohale (Formoterol Fumarate) Inhalation Solution:
  • more often than prescribed,
  • more medicine than prescribed for you, or
  • with other LABA medicines

Call your healthcare provider or get emergency medical care right away if:

• your breathing problems worsen with Triohale (Formoterol Fumarate) Inhalation Solution
• you need to use your rescue inhaler medicine more often than usual
• your rescue inhaler medicine does not work as well for you at relieving symptoms

What are the possible side effects of Triohale (Formoterol Fumarate) Inhalation Solution?

Triohale (Formoterol Fumarate) Inhalation Solution can cause serious side effects, including:

• See “What is the most important information I should know about Triohale (Formoterol Fumarate) Inhalation Solution?”
• Sudden shortness of breath immediately after use of Triohale (Formoterol Fumarate) Inhalation Solution.
• Serious allergic reactions including rash, hives, swelling of the face, mouth, and tongue, and breathing problems. Call your healthcare provider or get emergency medical care if you get any symptoms of a serious allergic reaction.
• chest pain
• increased or decreased blood pressure
• a fast and irregular heartbeat
• low blood potassium
• high blood sugar
• high blood acid

Common side effects of Triohale (Formoterol Fumarate) Inhalation Solution include:

• headache
• tremor
• nervousness
• dry mouth
• muscle cramps
• nausea, vomiting
• diarrhea
• dizziness
• tiredness
• trouble sleeping
• If your COPD symptoms worsen over time do not increase your dose of Triohale (Formoterol Fumarate) Inhalation Solution, instead call your healthcare provider.

Tell your healthcare provider if you get any side effect that bothers you or that does not go away.

These are not all the side effects with Triohale (Formoterol Fumarate) Inhalation Solution. Ask your healthcare provider or pharmacist for more information.

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

How should I store Triohale (Formoterol Fumarate) Inhalation Solution?

• Store Triohale (Formoterol Fumarate) Inhalation Solution in a refrigerator between 36° to 46°F (2^o to 8^oC) in the protective foil pouch. Protect from light and heat. Do not open a sealed pouch until you are ready to use a dose of Triohale (Formoterol Fumarate) Inhalation Solution. Once a sealed pouch is opened, Triohale (Formoterol Fumarate) Inhalation Solution must be used right away. Triohale (Formoterol Fumarate) Inhalation Solution may be used directly from the refrigerator.
• Triohale (Formoterol Fumarate) Inhalation Solution may also be stored at room temperature between 68ºF to 77ºF (20ºC to 25ºC) for up to 3 months (90 days). If stored at room temperature, discard Triohale (Formoterol Fumarate) Inhalation Solution if it is not used after 3 months or if past the expiration date, whichever is sooner. Space is provided on the packaging to record dispense date and use by date.
• Do not use Triohale (Formoterol Fumarate) Inhalation Solution after the expiration date provided on the foil pouch and vial.
• Triohale (Formoterol Fumarate) Inhalation Solution should be colorless. Discard Triohale (Formoterol Fumarate) Inhalation Solution if it is not colorless.
• Keep Triohale (Formoterol Fumarate) Inhalation Solution and all medicines out of the reach of children.

General Information about Triohale (Formoterol Fumarate) Inhalation Solution

Medicines are sometimes prescribed for purposes that are not mentioned in a Medication Guide. Do not use Triohale (Formoterol Fumarate) Inhalation Solution for a condition for which it was not prescribed. Do not give Triohale (Formoterol Fumarate) Inhalation Solution to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about Triohale (Formoterol Fumarate) Inhalation Solution. If you would like more information, talk with your health care provider. You can ask your health care provider or pharmacist for information about Triohale (Formoterol Fumarate) Inhalation Solution that was written for healthcare professionals.

• For customer service, call 1-800-395-3376
• To report side effects, call 1-877-446-3679
• For medical information, call 1-800-429-7751

Instructions for Using Triohale (Formoterol Fumarate) (formoterol fumarate) Inhalation Solution

Triohale (Formoterol Fumarate) Inhalation Solution is used only in a standard jet nebulizer machine connected to an air compressor. Make sure you know how to use your nebulizer machine before you use it to breathe in Triohale (Formoterol Fumarate) Inhalation Solution or other medicines.

Do not mix Triohale (Formoterol Fumarate) Inhalation Solution with other medicines in your nebulizer machine.

Triohale (Formoterol Fumarate) Inhalation Solution comes sealed in a foil pouch. Do not open a sealed pouch until you are ready to use a dose of Triohale (Formoterol Fumarate) Inhalation Solution.

• Remove vial from the foil pouch.
• Twist the cap completely off the vial and squeeze all the medicine into the nebulizer medicine cup (reservoir) (Figure 1).
  

• Connect the nebulizer reservoir to the mouthpiece or facemask (Figure 2).
• Connect the nebulizer to the compressor.
• Sit in a comfortable, upright position. Place the mouthpiece in your mouth (Figure 3) or put on the facemask (Figure 4); and turn on the compressor.
• Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer reservoir. The average nebulization time is 9 minutes. At this point, the treatment is finished.
• Discard the Triohale (Formoterol Fumarate) Inhalation Solution container and top after use.
• Clean the nebulizer.

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

Revised MARCH 2013

This Medication Guide has been approved by the U.S. Food and Drug Administration

A3-031-00

Figure 1 Figure 2 Figures 3 and 4

PRINCIPAL DISPLAY PANEL - 20 mcg/2 mL vial

NDC 49502-605-61

Triohale (Formoterol Fumarate)^®

(formoterol fumarate) INHALATION SOLUTION

20 mcg/2 mL vial

Medication Guide For Patients Enclosed

Sterile Unit Dose Vials - Individually Wrapped - For Oral Inhalation Only

CARTON CONTAINS: 60 individually wrapped 2 mL vials

EACH 2 mL VIAL CONTAINS: ACTIVE: Triohale (Formoterol Fumarate), USP.

INACTIVES: Citric acid, sodium citrate, sodium chloride, and water.

STORAGE CONDITIONS:

PRIOR TO DISPENSING TO THE PATIENT: Store refrigerated, 2°C to 8°C (36°F to 46°F).

AFTER DISPENSING TO THE PATIENT: Store at 2°C to 25°C (36°F to 77°F) for up to 3 months.

Protect pouch from heat. VIAL SHOULD ALWAYS BE STORED IN THE FOIL POUCH, AND ONLY REMOVED IMMEDIATELY BEFORE USE.

Keep out of reach of children.

FOR THE HEALTHCARE PROVIDER: When Triohale (Formoterol Fumarate)^® Inhalation Solution is dispensed to the patient, write an expiration date in the "Use by" box on the carton or dispensing container. The date should not exceed either 3 months from date dispensed or the expiration date on the product, whichever comes first. After dispensing to the patient, store at 2°C to 25°C (36°F to 77°F) for up to 3 months.

FOR THE PATIENT: Use Triohale (Formoterol Fumarate)^® Inhalation Solution prior to the "Use by" date.

Rx Only

U.S. Pat. Nos. 6,667,344 and 6,814,953

Mylan Specialty L.P., Morgantown, WV 26505

Manufactured for:

Mylan Specialty L.P.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

02-487-00

Triohale (Formoterol Fumarate) Inhalation Solution 20 mcg/2 mL Carton

Tiotropium Bromide:

•   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
• Triohale (Tiotropium Bromide) reviews

1  INDICATIONS AND USAGE

Triohale (Tiotropium Bromide) 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. Triohale (Tiotropium Bromide) HANDIHALERis indicated to reduce exacerbations in COPD patients.

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules should only be used with theHANDIHALER device [see Overdosage (10) ].

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

Foradministration of Triohale (Tiotropium Bromide) HANDIHALER, a Triohale (Tiotropium Bromide) capsule is placedinto the center chamber of the HANDIHALER device. The Triohale (Tiotropium Bromide) capsuleis pierced by pressing and releasing the green piercing button onthe side of the HANDIHALER device. The tiotropium 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules. Only use Triohale (Tiotropium Bromide) 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: Triohale (Tiotropium Bromide) HANDIHALER consistsof Triohale (Tiotropium Bromide) capsules containing tiotropium powder for oral inhalationand a HANDIHALER device. Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules.

Inhalation powder: Triohale (Tiotropium Bromide) capsules contain18 mcg tiotropium powder for use with HANDIHALER device (3)

4  CONTRAINDICATIONS

Triohale (Tiotropium Bromide) HANDIHALER is contraindicated in patients with a hypersensitivityto tiotropium, 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 tiotropium,ipratropium or any components of Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER. Ifsuch a reaction occurs, therapy with Triohale (Tiotropium Bromide) HANDIHALER should bestopped at once and alternative treatments should be considered. Giventhe similar structural formula of atropine to tiotropium, patientswith a history of hypersensitivity reactions to atropine or its derivativesshould be closely monitored for similar hypersensitivity reactionsto Triohale (Tiotropium Bromide) HANDIHALER. In addition, Triohale (Tiotropium Bromide) HANDIHALER should be usedwith caution in patients with severe hypersensitivity to milk proteins.

5.3  Paradoxical Bronchospasm

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

5.4  Worsening of Narrow-AngleGlaucoma

Triohale 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 (e.g., eye pain or discomfort, blurredvision, visual halos or colored images in association with red eyesfrom conjunctival congestion and corneal edema). Instruct patientsto consult a physician immediately should any of these signs or symptomsdevelop.

5.5  Worsening of UrinaryRetention

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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
	Triohale (Tiotropium Bromide) (n = 550)	Placebo (n = 371)	Triohale (Tiotropium Bromide) (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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALERin 5992 COPD patients in a 4-year placebo-controlled trial. In thistrial, 2986 patients were treated with Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale HANDIHALER with other anticholinergic-containing drugs. (7.2)

7.1  Sympathomimetics,Methylxanthines, Steroids

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 tiotropium doses of approximately 40 timesthe MRHDID (on a mcg/m² basis at a maternalinhalation dose of 78 mcg/kg/day). In rabbits, tiotropium 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 Triohale HANDIHALER has not been studiedduring 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 breastmilk. It is not known whether tiotropium is excreted in human milk,but because many drugs are excreted in human milk and given thesefindings in rats, caution should be exercised if Triohale (Tiotropium Bromide) HANDIHALERis administered to a nursing woman.

8.4  Pediatric Use

SPIRIVAHANDIHALER is not indicated for use in children. The safety and effectivenessof Triohale 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 treated with Triohale (Tiotropium Bromide) 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 tiotropium were not studied.

10  OVERDOSAGE

Highdoses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects followinga single inhaled dose of up to 282 mcg tiotropium 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 tiotropium.

Treatment of overdosage consists of discontinuation of Triohale (Tiotropium Bromide) HANDIHALERtogether with institution of appropriate symptomatic and/or supportivetherapy.

AccidentalIngestion

Acute intoxicationby inadvertent oral ingestion of Triohale (Tiotropium Bromide) 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, Triohale (Tiotropium Bromide) HANDIHALER was discontinued, and the constipationwas treated with an enema. The patient recovered and was dischargedon the same day.

11  DESCRIPTION

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

The contents of Triohale (Tiotropium Bromide) capsules are intended for oral inhalationonly, and are intended for administration only with the HANDIHALERdevice.

The active component ofSPIRIVA HANDIHALER is tiotropium. The drug substance, tiotropium 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. Triohale (Tiotropium 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 tiotropium 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 Triohale (Tiotropium Bromide) capsule outside the blister pack.

Triohale (Tiotropium Bromide) Structure

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

Tiotropium 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 tiotropium is predominantly a site-specificeffect.

12.2  Pharmacodynamics

Cardiac Electrophysiology

In amulticenter, randomized, double-blind trial using tiotropium 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 Triohale HANDIHALER group as compared withplacebo. This difference was apparent using both the Bazett (QTcB)[20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16(16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with Triohale (Tiotropium Bromide) HANDIHALER did not detect an effectof the drug on QTc intervals.

The effect of tiotropium 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 tiotropium 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

Tiotropium 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 tiotropium 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 tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium. Maximumtiotropium plasma concentrations were observed 7 minutes after inhalation.

Distribution

Tiotropium 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 tiotropium in COPD patients followingonce daily inhalation of 5 mcg tiotropium 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. Tiotropium, 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 tiotropium in supra-therapeuticconcentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6,2E1, or 3A4.

Excretion

Intravenously administered Triohale (Tiotropium 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 tiotropium 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 Triohale (Tiotropium Bromide) 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 tiotropium exposure inpatients with severe renal impairment (creatinine clearance <30mL/min) following inhalation of Triohale (Tiotropium Bromide) HANDIHALER or Triohale (Tiotropium Bromide) RESPIMAT.However AUC_0-4 and C_max were 94% and 52% higher, respectively, in patients with severe renalimpairment following intravenous infusion of Triohale (Tiotropium Bromide).

Hepatic Impairment

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

Drug Interactions

An interaction study with tiotropium (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 tiotropium resulted in a 20% increase in the AUC_0-4h, a 28% decrease in the renal clearance of tiotropium and no significantchange in the C_max and amount excreted in urineover 96 hours. Co-administration of tiotropium with ranitidine didnot affect the pharmacokinetics of tiotropium.

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

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was observedin a 104-week inhalation study in rats at tiotropium 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.

Triohale (Tiotropium 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 tiotropium 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 Triohale (Tiotropium Bromide) HANDIHALER (tiotropium bromide inhalation powder) clinicaldevelopment program consisted of six Phase 3 studies in 2663 patientswith COPD (1308 receiving Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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).

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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. Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER and placebo.

The all-cause mortality ofSPIRIVA HANDIHALER was also compared to tiotropium 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 Triohale (Tiotropium Bromide) RESPIMAT.

Figure 1 Figure 2 Figure 3

16  HOW SUPPLIED/STORAGEAND HANDLING

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

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

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

The following packages are available:

• carton containing 5 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules should not be exposedto extreme temperature or moisture. Do not store Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules should only be administeredvia the HANDIHALER device and the HANDIHALER device should not beused for administering other medications. Remind patients thatthe contents of Triohale (Tiotropium Bromide) capsules are for oral inhalation only andmust not be swallowed.

Instruct patients always to store SPIRIVAcapsules in sealed blisters and to remove only one Triohale (Tiotropium Bromide) capsuleimmediately before use or its effectiveness may be reduced. Instructpatients to discard unused additional Triohale (Tiotropium Bromide) 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

IT1600AGA72016

10004551/13

IT5300J

75740-09

Patient Information

Triohale (Tiotropium Bromide)^® (speh REE vah) HANDIHALER^®

(tiotropium bromide inhalation powder)

Do NOT swallowSPIRIVA capsules.

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

Read the informationthat comes with your Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER?

• Triohale (Tiotropium Bromide) HANDIHALER is a prescription medicine used eachday (a maintenance medicine) to control symptoms of chronic obstructivepulmonary disease (COPD), including chronic bronchitis and emphysema.
• Triohale (Tiotropium Bromide) HANDIHALER helps make your lungs work better for24 hours. Triohale (Tiotropium Bromide) 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. Triohale (Tiotropium Bromide) HANDIHALER works best and may help make it easierto breathe when you use it every day.
• Triohale (Tiotropium Bromide) 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.

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER is safe and effectivein children.

Whoshould not take Triohale (Tiotropium Bromide) HANDIHALER?

Do not use Triohale (Tiotropium Bromide) HANDIHALER if you:

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

Symptoms of a serious allergic reactionto Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER and call your doctorright away or go to the nearest hospital emergency room.

What should I tell my doctorbefore using Triohale (Tiotropium Bromide) HANDIHALER?

Before taking Triohale (Tiotropium Bromide) HANDIHALER, tellyour doctor about all your medical conditions, including if you:

• have kidney problems.
• have glaucoma. Triohale (Tiotropium Bromide) HANDIHALER may make your glaucomaworse.
• have an enlarged prostate, problems passing urine, or ablockage in your bladder. Triohale (Tiotropium Bromide) HANDIHALER may make these problemsworse.
• are pregnant or plan to become pregnant. It is not knownif Triohale (Tiotropium Bromide) HANDIHALER could harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not knownif Triohale (Tiotropium Bromide) HANDIHALER passes into breast milk. You and your doctorwill decide if Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER works. Triohale (Tiotropium Bromide) HANDIHALER is an anticholinergicmedicine. You should not take other anticholinergic medicines whileusing Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER?

• Use Triohale (Tiotropium Bromide) HANDIHALER exactly as prescribed. Use SPIRIVAHANDIHALER one time every day.
• Read the "Instructions for Use" at the end of this leafletbefore you use Triohale (Tiotropium Bromide) HANDIHALER. Talk with your doctor if you donot understand the instructions.
• Do not swallow Triohale (Tiotropium Bromide) capsules.
• Only use Triohale (Tiotropium Bromide) capsules with the HANDIHALER device.
• Do not use the HANDIHALER device to take any othermedicine.
• Triohale (Tiotropium Bromide) HANDIHALER comes as a powder in a Triohale (Tiotropium Bromide) capsulethat fits the HANDIHALER device. Each Triohale (Tiotropium Bromide) capsule, containingonly a small amount of Triohale (Tiotropium Bromide) powder, is one full dose of medicine.
• Separate one blister from the blister card. Then take outone of the Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsule). Seethe " Instructions for Use " at theend of this leaflet.
• Throw away any Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER more than one time every 24 hours.
• If you use more than your prescribed dose of Triohale (Tiotropium Bromide) HANDIHALER,call your doctor or a poison control center.

What should I avoidwhile using Triohale (Tiotropium Bromide) HANDIHALER?

• Do not let the powder from the Triohale (Tiotropium Bromide) capsule get intoyour eyes. Your vision may get blurry and the pupil in your eye mayget larger (dilate). If this happens, call your doctor.
• Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER?

Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules in the HANDIHALERdevice.
• Store Triohale (Tiotropium Bromide) capsules in the sealed blister package atroom temperature between 68°F to 77°F (20°C to 25°C).
• Keep Triohale (Tiotropium Bromide) capsules away from heat and cold (do not freeze).
• Store Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules.

Keep Triohale (Tiotropium Bromide) HANDIHALER,SPIRIVA capsules, and all medicines out of the reach of children.

Generalinformation about Triohale (Tiotropium Bromide) HANDIHALER

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

For more informationabout Triohale (Tiotropium Bromide) HANDIHALER, talk with your doctor. You can ask yourdoctor or pharmacist for information about Triohale (Tiotropium Bromide) HANDIHALER thatis written for health professionals.

For more information about Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HANDIHALER?

Active ingredient: tiotropium

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

Triohale (Tiotropium Bromide)^® 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 Triohale (Tiotropium Bromide) HANDIHALER

• Do not swallow Triohale (Tiotropium Bromide) capsules.
• Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules:

Your Triohale (Tiotropium Bromide) HANDIHALERcomes with Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsule ispackaged in a blister.
	Each Triohale (Tiotropium Bromide) capsule contains only a small amount of powder. This is 1 full dose. Do not open the Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsule. Make sure you breathe outcompletely each time before you breathe in from your HANDIHALER device.
Caring forand storing your Triohale (Tiotropium Bromide) HANDIHALER:
	After taking your daily dose, open the mouthpiece and tipout the used Triohale (Tiotropium Bromide) capsule into your trash can, without touchingit. Remove any Triohale (Tiotropium Bromide) capsule pieces or Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsules (blisters) in a damp moist place. Alwaysstore Triohale (Tiotropium Bromide) capsules in the sealed blisters.
If you do nothear or feel the Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) capsule rattle after repeating theabove steps: Throw away the Triohale (Tiotropium Bromide) capsule. Open the base by lifting the green piercing button and checkthe center chamber for pieces of the Triohale (Tiotropium Bromide) capsule. Triohale (Tiotropium Bromide) capsulepieces in the center chamber can cause a Triohale (Tiotropium Bromide) capsule not to rattle. Turn your HANDIHALER device upside down and gently, butfirmly, tap to remove the Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) Instructions for Triohale (Tiotropium Bromide) 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 Triohale (Tiotropium Bromide) HandiHaler

30 capsules (3 blister cards)

1 HandiHaler InhalationDevice

NDC 0597-0075-41

spiriva-hh-ndc-0597-0075-41 Triohale (Tiotropium Bromide) HandiHaler

90 capsules(9 blister cards)

1 HandiHaler Inhalation Device

NDC 0597-0075-47

spiriva-hh-ndc-0597-0075-47 Triohale (Tiotropium Bromide) HandiHaler

5 capsules(1 blister card)

1 HandiHaler Inhalation Device

NDC 0597-0075-75

spiriva-hh-ndc-0597-0075-75 Triohale (Tiotropium Bromide) HandiHaler

ProfessionalSample

10 capsules (1 blister card)

1 HandiHalerInhalation Device

NDC 0597-0075-27

spiriva-hh-ndc-0597-0075-27