NDC 0597-0155 Stiolto Respimat

Tiotropium Bromide And Olodaterol

NDC Product Code 0597-0155

NDC CODE: 0597-0155

Proprietary Name: Stiolto Respimat What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Tiotropium Bromide And Olodaterol What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This product is used to control and prevent symptoms (such as wheezing and shortness of breath) caused by ongoing lung disease (chronic obstructive pulmonary disease-COPD, which includes chronic bronchitis and emphysema). Controlling symptoms of breathing problems helps you stay active. This inhaler contains 2 medications: tiotropium and olodaterol. Both drugs work by relaxing the muscles around the airways so that they open up and you can breathe more easily. Tiotropium belongs to a class of drugs known as anticholinergics. Olodaterol belongs to the class of drugs known as long-acting inhaled beta-agonists (LABAs). Both drugs are also known as bronchodilators. This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden shortness of breath. If sudden breathing problems occur, use your quick-relief inhaler as prescribed. Tiotropium/olodaterol is not approved to treat asthma. People with asthma using long-acting inhaled beta agonists (such as olodaterol) without also using an inhaled corticosteroid may have an increased risk of serious (sometimes fatal) breathing problems.

NDC Code Structure

NDC 0597-0155-28

Package Description: 1 CARTRIDGE in 1 CARTON > 28 SPRAY, METERED in 1 CARTRIDGE

NDC 0597-0155-31

Package Description: 1 CARTRIDGE in 1 CARTON > 28 SPRAY, METERED in 1 CARTRIDGE

NDC 0597-0155-61

Package Description: 1 CARTRIDGE in 1 CARTON > 60 SPRAY, METERED in 1 CARTRIDGE

NDC 0597-0155-70

Package Description: 1 CARTRIDGE in 1 CARTON > 10 SPRAY, METERED in 1 CARTRIDGE

NDC Product Information

Stiolto Respimat with NDC 0597-0155 is a a human prescription drug product labeled by Boehringer Ingelheim Pharmaceuticals Inc.. The generic name of Stiolto Respimat is tiotropium bromide and olodaterol. The product's dosage form is spray, metered and is administered via respiratory (inhalation) form.

Labeler Name: Boehringer Ingelheim Pharmaceuticals Inc.

Dosage Form: Spray, Metered - A non-pressurized dosage form consisting of valves which allow the dispensing of a specified quantity of spray upon each activation.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Stiolto Respimat Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TIOTROPIUM BROMIDE MONOHYDRATE 3.124 ug/1
  • OLODATEROL HYDROCHLORIDE 2.736 ug/1

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Respiratory (inhalation) - Administration within the respiratory tract by inhaling orally or nasally for local or systemic effect.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Anticholinergic - [EPC] (Established Pharmacologic Class)
  • Cholinergic Antagonists - [MoA] (Mechanism of Action)
  • beta2-Adrenergic Agonist - [EPC] (Established Pharmacologic Class)
  • Adrenergic beta2-Agonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Boehringer Ingelheim Pharmaceuticals Inc.
Labeler Code: 0597
FDA Application Number: NDA206756 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-21-2015 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Olodaterol Oral Inhalation

Olodaterol Oral Inhalation is pronounced as (oh'' loe da' ter ol)

Why is olodaterol oral inhalation medication prescribed?
Olodaterol oral inhalation is used to control wheezing, shortness of breath, coughing, and chest tightness caused by chronic obstructive pulmonary disease (COPD; a group ...
[Read More]

* Please review the disclaimer below.

Stiolto Respimat Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Long-acting beta2-adrenergic agonists
(LABA) such as olodaterol, one of the active ingredients in STIOLTO
RESPIMAT, 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) with
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 all LABA, including olodaterol, one
of the active ingredients in STIOLTO RESPIMAT. The safety and efficacy
of STIOLTO RESPIMAT in patients with asthma have not been established.
STIOLTO RESPIMAT is not indicated for the treatment of asthma [see Contraindications (4), Warnings
and Precautions (5.1)].

1.1 Maintenance Treatment Of Copd

  • STIOLTO RESPIMAT is a combination of tiotropium
  • And olodaterol indicated for long-term, once-daily maintenance treatment
  • Of airflow obstruction in patients with chronic obstructive pulmonary
  • Disease (COPD), including chronic bronchitis and/or emphysema.Important Limitations
  • Of Use STIOLTO RESPIMAT is not indicated to treat acute deteriorations
  • Of COPD [See Warnings and Precautions (5.2)]. STIOLTO RESPIMAT is not indicated to treat asthma. The
  • Safety and effectiveness of STIOLTO RESPIMAT in asthma have not been
  • Established.

The recommended dose of STIOLTO RESPIMAT is
two inhalations once-daily at the same time of the day. Do not use
STIOLTO RESPIMAT more than two inhalations every 24 hours.

2.2 Administration Information

For oral inhalation only.Prior to first use, the STIOLTO
RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and
the unit is primed. When using the unit for the first time, patients
are to actuate the inhaler toward the ground until an aerosol cloud
is visible and then repeat the process three more times. The unit
is then considered primed and ready for use. If not used for more
than 3 days, patients are to actuate the inhaler once to prepare the
inhaler for use. If not used for more than 21 days, patients are to
actuate the inhaler until an aerosol cloud is visible and then repeat
the process three more times to prepare the inhaler for use [see Patient Counseling Information (17)].No dosage
adjustment is required for geriatric, hepatically-impaired, or renally-impaired
patients. However, patients with moderate to severe renal impairment
given STIOLTO RESPIMAT should be monitored closely for anticholinergic
effects [see Warnings and Precautions (5.9), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)].

3  Dosage Forms And Strengths

Inhalation
Spray: STIOLTO RESPIMAT consists of a STIOLTO RESPIMAT inhaler and
an aluminum cylinder (STIOLTO RESPIMAT cartridge) containing a combination
of tiotropium bromide (as the monohydrate) and olodaterol (as the
hydrochloride). The STIOLTO RESPIMAT cartridge is intended only for
use with the STIOLTO RESPIMAT inhaler.Each actuation from the STIOLTO RESPIMAT
inhaler delivers 3.124 mcg tiotropium bromide monohydrate (equivalent
to 2.5 mcg tiotropium) and 2.736 mcg olodaterol hydrochloride (equivalent
to 2.5 mcg olodaterol) from the mouthpiece.Two actuations equal one dose.

4  Contraindications

All LABAs are contraindicated in patients with asthma without
use of a long-term asthma control medication [see Warnings
and Precautions (5.1)].
STIOLTO RESPIMAT is not indicated for the treatment of asthma.STIOLTO RESPIMAT is contraindicated
in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol,
or any component of this product [see Warnings and Precautions
(5.4)].In clinical trials and postmarketing experience
with tiotropium, immediate hypersensitivity reactions, including angioedema
(including swelling of the lips, tongue, or throat), itching, or rash
have been reported. Hypersensitivity reactions were also reported
in clinical trials with STIOLTO RESPIMAT.

  • 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 another long-acting beta2-adrenergic agonist
  • (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 long-acting
  • Beta2-adrenergic agonists, including olodaterol,
  • One of the active ingredients in STIOLTO RESPIMAT. No study adequate
  • To determine whether the rate of asthma-related death is increased
  • In patients treated with STIOLTO RESPIMAT has been conducted. The
  • Safety and efficacy of STIOLTO RESPIMAT in patients with asthma have
  • Not been established. STIOLTO RESPIMAT is not indicated for the treatment
  • Of asthma [See Contraindications (4)].

5.2 Deterioration Of Disease And Acute Episodes

STIOLTO RESPIMAT should not be
initiated in patients with acutely deteriorating COPD, which may be
a life-threatening condition. STIOLTO RESPIMAT has not been studied
in patients with acutely deteriorating COPD. The use of STIOLTO RESPIMAT
in this setting is inappropriate. STIOLTO RESPIMAT should not be used for the
relief of acute symptoms, i.e., as rescue therapy for the treatment
of acute episodes of bronchospasm. STIOLTO RESPIMAT 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 STIOLTO RESPIMAT, 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
STIOLTO RESPIMAT, the healthcare provider should also prescribe an
inhaled, short-acting beta2-agonist and instruct
the patient on 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 STIOLTO RESPIMAT
no longer controls 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 STIOLTO RESPIMAT beyond the recommended
dose is not appropriate in this situation.

5.3 Excessive Use Of Stiolto Respimat And Use With Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, STIOLTO RESPIMAT should not be used
more often than recommended, 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 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including
urticaria, angioedema (including swelling of the lips, tongue or throat),
rash, bronchospasm, anaphylaxis, or itching may occur after administration
of STIOLTO RESPIMAT. If such a reaction occurs, therapy with STIOLTO
RESPIMAT should be stopped at once and alternative treatments should
be considered. Given the similar structural formula of atropine to
tiotropium, patients with a history of hypersensitivity reactions
to atropine or its derivatives should be closely monitored for similar
hypersensitivity reactions to STIOLTO RESPIMAT.

5.5 Paradoxical Bronchospasm

As with other inhaled medicines, STIOLTO RESPIMAT
may cause paradoxical bronchospasm that may be life-threatening. If
paradoxical bronchospasm occurs, STIOLTO RESPIMAT should be stopped
immediately and alternative therapy instituted.

5.6 Cardiovascular Effects

Olodaterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect
in some patients as measured by increases in pulse rate, systolic
or diastolic blood pressure, and/or symptoms. If such effects occur,
STIOLTO RESPIMAT 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. Long acting
beta2-adrenergic agonists should be administered
with caution in patients with cardiovascular disorders, especially
coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive
cardiomyopathy, and hypertension.

5.7 Coexisting Conditions

Olodaterol, like other sympathomimetic amines,
should be used with caution in patients with convulsive disorders
or thyrotoxicosis, in patients with known or suspected prolongation
of the QT interval, 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 pre-existing diabetes mellitus and ketoacidosis.

5.8 Worsening Of Narrow-Angle Glaucoma

STIOLTO RESPIMAT should be used with caution
in patients with narrow-angle glaucoma. Prescribers and patients should
be alert for signs and symptoms of acute narrow-angle glaucoma (e.g.,
eye pain or discomfort, blurred vision, visual halos or colored images
in association with red eyes from conjunctival congestion and corneal
edema). Instruct patients to consult a physician immediately should
any of these signs or symptoms develop.

5.9 Worsening Of Urinary Retention

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

5.10 Renal Impairment

Because tiotropium is a predominantly
renally excreted drug, patients with moderate to severe renal impairment
(creatinine clearance of <60 mL/min) treated with STIOLTO RESPIMAT
should be monitored closely for anticholinergic side effects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

5.11 Hypokalemia And Hyperglycemia

Beta-adrenergic agonists may produce significant
hypokalemia in some patients, which has the potential to produce adverse
cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum
potassium is usually transient, not requiring supplementation. Inhalation
of high doses of beta2-adrenergic agonists
may produce increases in plasma glucose. In patients with severe COPD, hypokalemia
may be potentiated by hypoxia and concomitant treatment [see
Drug Interactions (7.2)],
which may increase the susceptibility for cardiac arrhythmias.Clinically notable decreases
in serum potassium or changes in blood glucose were infrequent during
clinical studies with long-term administration of olodaterol with
the rates similar to those for placebo controls. Olodaterol has not
been investigated in patients whose diabetes mellitus is not well
controlled.

6  Adverse Reactions

  • LABA, such as olodaterol, one of the active components
  • In STIOLTO RESPIMAT, increase the risk of asthma-related death. STIOLTO
  • RESPIMAT is not indicated for the treatment of asthma [see
  • Boxed Warning and Warning and Precautions 5.1].The following adverse reactions are described, or described in greater
  • Detail, in other sections: Immediate hypersensitivity reactions [see Warnings
  • And Precautions (5.4)]Paradoxical bronchospasm [see Warnings and Precautions
  • (5.5)]Worsening of narrow-angle glaucoma [see Warnings
  • And Precautions (5.7)]Worsening of urinary retention [see Warnings and
  • Precautions (5.8)]

6.1 Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

Because clinical trials are conducted under
widely varying conditions, the incidence of adverse reactions observed
in the clinical trials of a drug cannot be directly compared to the
incidences in the clinical trials of another drug and may not reflect
the incidences observed in practice.The clinical program for STIOLTO RESPIMAT
included 7151 subjects with COPD in two 52-week active-controlled
trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled
cross-over trials, and four additional trials of shorter duration.
A total of 1988 subjects received at least 1 dose of STIOLTO RESPIMAT.
Adverse reactions observed in the ≤12-week trials were consistent
with those observed in the 52-week trials, which formed the primary
safety database.The
primary safety database consisted of pooled data from the two 52-week
double-blind, active-controlled, parallel group confirmatory clinical
trials. These trials included 5162 adult COPD patients (72.9% males
and 27.1% females) 40 years of age and older. Of these patients, 1029
were treated with STIOLTO RESPIMAT once daily. The STIOLTO RESPIMAT
group was composed of mostly Caucasians (71.1%) with a mean age of
63.8 years and a mean percent predicted FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and
olodaterol 5 mcg were included as active control arms and no placebo
was used. In these
two clinical trials, 74% of patients exposed to STIOLTO RESPIMAT reported
an adverse reaction compared to 76.6% and 73.3% in the olodaterol
5 mcg and tiotropium 5 mcg groups, respectively. The proportion of
patients who discontinued due to an adverse reaction was 7.4% for
STIOLTO RESPIMAT treated patients compared to 9.9% and 9.0% for olodaterol
5 mcg and tiotropium 5 mcg treated patients. The adverse reaction
most commonly leading to discontinuation was worsening COPD.The most common serious adverse
reactions were COPD exacerbation and pneumonia. Table 1 shows all adverse drug reactions that
occurred with an incidence of >3% in the STIOLTO RESPIMAT treatment
group and a higher incidence rate than the active comparator groups
listed. Table 1  Number and frequency of adverse drug reactions greater
than 3% (and higher than any of the comparators tiotropium and/or
olodaterol) in COPD patients exposed to STIOLTO RESPIMAT: Pooled data
from the two 52-week, double-blind, active-controlled clinical trials
in COPD patients 40 years of age and olderTreatmentSTIOLTO RESPIMAT(once daily)Tiotropium(5 mcg once daily)Olodaterol(5 mcg once daily)Body system (adverse drug
reaction)n=1029n (%)n=1033n (%)n=1038n (%)Infections and
infestations     Nasopharyngitis128 (12.4)121 (11.7)131 (12.6)Respiratory, thoracic,
and mediastinal disorders     Cough40 (3.9)45 (4.4)31 (3.0)Musculoskeletal
and connective tissue disorders     Back Pain37 (3.6)19 (1.8)35 (3.4)Other adverse drug reactions
in patients receiving STIOLTO RESPIMAT that occurred in ≤3% of patients
in clinical studies are listed below: Metabolism and nutrition disorders: dehydrationNervous system disorders: dizziness, insomniaEye disorders: glaucoma,
intraocular pressure increased, vision blurredCardiac/vascular disorders: atrial fibrillation, palpitations,
supraventricular tachycardia, tachycardia, hypertensionRespiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitisGastrointestinal disorders: dry mouth, constipation,
oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease,
gingivitis, glossitis, stomatitis, intestinal obstruction including
ileus paralyticSkin and subcutaneous disorders: rash, pruritus, angioneurotic edema, urticaria, skin infection,
and skin ulcer, dry skin, hypersensitivity (including immediate reactions)Musculoskeletal and connective tissue disorders: arthralgia, joint swelling Renal and urinary
disorders: urinary retention, dysuria, and urinary tract
infection

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 olodaterol, one component of STIOLTO RESPIMAT
may be potentiated [see Warnings and Precautions (5.3, 5.6, 5.10, 5.11)].

7.2 Sympathomimetics, Xanthine Derivatives, Steroids, Or Diuretics

Tiotropium has been used concomitantly with
short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators,
methylxanthines, and oral and inhaled steroids, without increases
in adverse reactions. Concomitant treatment with xanthine derivatives,
steroids, or diuretics may potentiate any hypokalemic effect of olodaterol [see Warnings and Precautions (5.11)].

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 STIOLTO RESPIMAT with
non-potassium sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, Qtc Prolonging Drugs

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

7.5 Beta-Blockers

Beta-adrenergic receptor antagonists (beta-blockers)
and the olodaterol component of STIOLTO RESPIMAT may interfere with
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.

7.6 Anticholinergics

There is potential for an additive
interaction with concomitantly used anticholinergic medications. Therefore,
avoid co-administration of STIOLTO RESPIMAT with other anticholinergic-containing
drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.7, 5.8) and Adverse Reactions (6)].

7.7 Inhibitors Of Cytochrome P450 And P-Gp Efflux Transporter

In a drug interaction study using
the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase
of olodaterol maximum plasma concentrations and AUC was observed [see Pharmacokinetics (12.3)]. Olodaterol was evaluated in clinical trials for up to one year
at doses up to twice the recommended therapeutic dose. No dose adjustment
of STIOLTO RESPIMAT is necessary.

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies with STIOLTO RESPIMAT
or its individual components, tiotropium bromide and olodaterol, in
pregnant women. Animal reproduction studies were conducted with the
individual components of STIOLTO RESPIMAT, tiotropium bromide and
olodaterol. STIOLTO RESPIMAT should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.TiotropiumNo
evidence of structural alterations was observed in rats and rabbits
at approximately 790 and 8 times the recommended human daily inhalation
dose (RHDID; on a mcg/m2 basis at maternal
inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively).
However, in rats, tiotropium caused fetal resorption, litter loss,
decreases in the number of live pups at birth and the mean pup weights,
and a delay in pup sexual maturation at approximately 40 times the
RHDID (on a mcg/m2 basis at a maternal
inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an
increase in post-implantation loss at approximately 430 times the
RHDID (on a mcg/m2 basis at a maternal
inhalation dose of 400 mcg/kg/day). Such effects were not observed
at approximately 5 and 95 times the RHDID (on a mcg/m2 basis at maternal inhalation doses of 9 and 88 mcg/kg/day
in rats and rabbits, respectively).OlodaterolOlodaterol was not teratogenic in rats at approximately 2731 times
the RHDID (on an AUC basis at a maternal inhalation dose of 1054 mcg/kg/day).
Placental transfer of olodaterol was observed in pregnant rats.Olodaterol has been shown to
be teratogenic in New Zealand rabbits at approximately 7130 times
the RHDID in adults (on an AUC basis at a maternal inhalation dose
of 2489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities:
enlarged or small heart atria or ventricles, eye abnormalities, and
split or distorted sternum. No significant effects occurred at approximately
1353 times the RHDID in adults (on an AUC basis at a maternal inhalation
dose of 974 mcg/kg/day).

8.2 Labor And Delivery

There are no adequate and well-controlled
human studies that have investigated the effects of STIOLTO RESPIMAT
on preterm labor or labor at term. Because of the potential for beta-agonist
interference with uterine contractility, use of STIOLTO RESPIMAT during
labor should be restricted to those patients in whom the benefits
clearly outweigh the risks.

8.3 Nursing Mothers

Clinical data from nursing women or infants exposed to STIOLTO
RESPIMAT or its individual active components are not available. Tiotropium,
olodaterol, and metabolites of olodaterol are excreted into the milk
of lactating rats. It is not known whether these compounds are excreted
in human milk, but because many drugs are excreted in human milk and
given these findings in rats, caution should be exercised if STIOLTO
RESPIMAT is administered to a nursing woman.

8.4 Pediatric Use

COPD does not normally occur in children. The safety and
effectiveness of STIOLTO RESPIMAT in the pediatric population has
not been established.

8.5 Geriatric Use

Based on available data, no adjustment of STIOLTO RESPIMAT
dosage in geriatric patients is warranted [see Clinical Pharmacology
(12.3)].Of the 1029 patients who received STIOLTO
RESPIMAT at the recommended dose once daily in the clinical studies
from the pooled 1-year database, 525 (51.0%) were <65 years of
age, 407 (39.6%) were 65 to <75, 96 (9.3%) were 75 to <85, and
1 (0.1%) was ≥85. No overall differences in effectiveness were observed, and in the
1-year pooled data, the adverse drug reaction profiles were similar
in the older population compared to the patient population overall.

8.6 Hepatic Impairment

No dose adjustment is needed
in patients with mild and moderate hepatic impairment. A study in
subjects with severe hepatic impairment was not performed [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is required
for patients with renal impairment. However, patients with moderate
to severe renal impairment (creatinine clearance of <60 mL/min)
treated with STIOLTO RESPIMAT should be monitored closely for anticholinergic
side effects [see Dosage and Administration (2), Warnings and Precautions (5.9), and Clinical Pharmacology (12.3)].

10  Overdosage

STIOLTO RESPIMAT contains both tiotropium bromide and olodaterol;
therefore, the risks associated with overdosage for the individual
components described below apply to STIOLTO RESPIMAT.TiotropiumHigh doses of tiotropium may lead to anticholinergic signs and symptoms.
However, there were no systemic anticholinergic adverse effects following
a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers.
In a study of 12 healthy volunteers, bilateral conjunctivitis and
dry mouth were seen following repeated once-daily inhalation of 141
mcg of tiotropium. Dry mouth/throat and dry nasal mucosa occurred
in a dose-dependent [10-40 mcg daily] manner, were observed following
14-day dosing of up to 40 mcg tiotropium bromide inhalation solution
in healthy subjects.OlodaterolThe expected signs and
symptoms with overdosage of olodaterol are those of excessive beta-adrenergic
stimulation and occurrence or exaggeration of any of the signs and
symptoms, e.g., myocardial ischemia, angina pectoris, hypertension
or hypotension, tachycardia, arrhythmias, palpitations, dizziness,
nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle
spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and
metabolic acidosis. As with all inhaled sympathomimetic medications,
cardiac arrest and even death may be associated with an overdose of
olodaterol.Treatment
of overdosage consists of discontinuation of STIOLTO RESPIMAT together
with institution of appropriate symptomatic and 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 STIOLTO RESPIMAT. Cardiac monitoring is recommended
in cases of overdosage.

11  Description

STIOLTO RESPIMAT is a combination of tiotropium,
an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA).The drug substance tiotropium bromide monohydrate
is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic,
non-chiral, quaternary ammonium compound. Tiotropium bromide is a
white or yellowish white powder. It is sparingly soluble in water
and soluble in methanol. The structural formula is:Tiotropium bromide (monohydrate) has a molecular
mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.The drug substance olodaterol hydrochloride
is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-,
monohydrochloride. Olodaterol hydrochloride is a white to off-white
powder that is sparingly-slightly soluble in water and slightly soluble
in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole
(base), and the molecular formula is C21H26N2O5 x
HCl as a hydrochloride. The conversion factor from salt to free base
is 1.094. The structural
formula is:The drug product, STIOLTO RESPIMAT, is composed
of a sterile aqueous solution of tiotropium bromide and olodaterol
hydrochloride filled into a 4.5 mL plastic container crimped into
an aluminum cylinder (STIOLTO RESPIMAT cartridge) for use with the
STIOLTO RESPIMAT inhaler.Excipients include water for injection,
benzalkonium chloride, edetate disodium, and hydrochloric acid.The STIOLTO RESPIMAT cartridge
is only intended for use with the STIOLTO RESPIMAT inhaler. The STIOLTO
RESPIMAT inhaler is a hand held, pocket sized oral inhalation device
that uses mechanical energy to generate a slow-moving aerosol cloud
of medication from a metered volume of the drug solution. The STIOLTO
RESPIMAT inhaler has a light green-colored cap. When used with the STIOLTO RESPIMAT inhaler
each cartridge, containing 4 grams of sterile aqueous solution, delivers
the labeled number of metered actuations after preparation for use.
Each dose (one dose equals two actuations) from the STIOLTO RESPIMAT
inhaler delivers 5 mcg tiotropium and 5 mcg olodaterol in 22.1 mcL
from the mouthpiece. As with all inhaled drugs, the actual amount
of drug delivered to the lung may depend on patient factors, such
as the coordination between the actuation of the inhaler and inspiration
through the delivery system. The duration of inspiration should be
at least as long as the spray duration (1.5 seconds).

12.1 Mechanism Of Action

STIOLTO RESPIMATSTIOLTO
RESPIMAT contains both tiotropium and olodaterol. The properties described
below for the individual components apply to STIOLTO RESPIMAT. These
drugs represent 2 different classes of medication (an anticholinergic
and a beta-agonist) that have different effects on clinical and physiological
indices.TiotropiumTiotropium is a long-acting, muscarinic
antagonist which is often referred to as an anticholinergic. It has
similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits
pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive
and reversible nature of antagonism was shown with human and animal
origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention
of methacholine-induced bronchoconstriction effects was dose-dependent
and lasted longer than 24 hours. The bronchodilation following inhalation
of tiotropium is predominantly a site-specific effect. OlodaterolOlodaterol is a long-acting beta2-adrenergic agonist (LABA). The compound exerts its pharmacological
effects by binding and activation of beta2-adrenoceptors
after topical administration by inhalation. Activation of these receptors
in the airways results in a stimulation of intracellular adenyl cyclase,
an enzyme that mediates the synthesis of cyclic-3’, 5’ adenosine monophosphate
(cAMP). Elevated levels of cAMP induce bronchodilation by relaxation
of airway smooth muscle cells. In vitro studies have
shown that olodaterol has 241-fold greater agonist activity at beta2-adrenoceptors compared to beta1-adrenoceptors and 2299-fold greater agonist activity compared to
beta3-adrenoceptors. The clinical significance
of these findings is unknown. Beta-adrenoceptors are divided into three
subtypes: beta1-adrenoceptors predominantly
expressed on cardiac muscle, beta2-adrenoceptors
predominantly expressed on airway smooth muscle, and beta3-adrenoceptors predominantly expressed on adipose tissue.
Beta2-agonists cause bronchodilation. Although
the beta2-adrenoceptor is the predominant adrenergic
receptor in the airway smooth muscle, it is also present on the surface
of a variety of other cells, including lung epithelial and endothelial
cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the
possibility that even highly selective beta2-agonists may have cardiac effects.

12.2 Pharmacodynamics

Cardiac ElectrophysiologySTIOLTO RESPIMATIn two 52-week
randomized, double-blind trials using STIOLTO RESPIMAT that enrolled
5162 patients with COPD, ECG assessments were performed post-dose
on days 1, 85, 169, and 365. In a pooled analysis the number of subjects
with changes from baseline-corrected QT interval of >30 msec using
both the Bazett (QTcB) and Fredericia (QTcF), corrections of QT for
heart rate were not different for the STIOLTO RESPIMAT group compared
to olodaterol 5 mcg and tiotropium 5 mcg across the assessments conducted.TiotropiumThe effect of tiotropium dry powder for inhalation on QT interval
was also evaluated in a randomized, placebo- and positive-controlled
crossover study in 53 healthy volunteers. Subjects received tiotropium
inhalation powder 18 mcg, 54 mcg (3 times the recommended dose), or
placebo for 12 days. ECG assessments were performed at baseline and
throughout the dosing interval following the first and last dose of
study medication. Relative to placebo, the maximum mean change from
baseline in study-specific QTc interval was 3.2 msec and 0.8 msec
for tiotropium inhalation powder 18 mcg and 54 mcg, respectively.
No subject showed a new onset of QTc >500 msec or QTc changes from
baseline of ≥60 msec.In a multicenter, randomized, double-blind trial using tiotropium
dry powder for inhalation that enrolled 198 patients with COPD, the
number of subjects with changes from baseline-corrected QT interval
of 30–60 msec was higher in the tiotropium group as compared with
placebo. 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 trials with tiotropium did not detect an effect of
the drug on QTc intervals.OlodaterolThe
effect of olodaterol on the QT/QTc interval of the ECG was investigated
in 24 healthy male and female volunteers in a double-blind, randomized,
placebo- and active (moxifloxacin)- controlled study at single doses
of 10, 20, 30, and 50 mcg. Dose-dependent QtcI (individual subject
corrected QT interval) prolongation was observed. The maximum mean
(one-sided 95% upper confidence bound) difference in QTcI from placebo
after baseline correction was 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7)
ms, and 8.5 (11.6) ms following doses of 10, 20, 30, and 50 mcg, respectively.The effect of 5 mcg and 10 mcg
olodaterol on heart rate and rhythm was assessed using continuous
24-hour ECG recording (Holter monitoring) in a subset of 772 patients
in the 48-week, placebo-controlled phase 3 trials. There were no dose-
or time-related trends or patterns observed for the magnitudes of
mean changes in heart rate or premature beats. Shifts from baseline
to the end of treatment in premature beats did not indicate meaningful
differences between olodaterol 5 mcg, 10 mcg, and placebo.

12.3 Pharmacokinetics

STIOLTO RESPIMATWhen STIOLTO RESPIMAT was
administered by the inhalation route, the pharmacokinetic parameters
for tiotropium and for olodaterol were similar to those observed when
each active substance was administered separately. TiotropiumTiotropium is administered as an inhalation spray. Some of the pharmacokinetic
data described below were obtained with higher doses than recommended
for therapy.OlodaterolOlodaterol showed linear pharmacokinetics.
On repeated once-daily inhalation, steady-state of olodaterol plasma
concentrations was achieved after 8 days, and the extent of exposure
was increased up to 1.8-fold as compared to a single dose.AbsorptionTiotropiumFollowing inhalation
of the solution by young healthy volunteers, urinary excretion data
suggests that approximately 33% of the inhaled dose reaches the systemic
circulation. Oral solutions of tiotropium have an absolute bioavailability
of 2% to 3%. Food is not expected to influence the absorption of tiotropium
for the same reason. Maximum tiotropium plasma concentrations were
observed 5 to 7 minutes after inhalation.OlodaterolOlodaterol
reaches maximum plasma concentrations generally within 10 to 20 minutes
following drug inhalation. In healthy volunteers the absolute bioavailability
of olodaterol following inhalation was estimated to be approximately
30%, whereas the absolute bioavailability was below 1% when given
as an oral solution. Thus, the systemic availability of olodaterol
after inhalation is mainly determined by lung absorption, while any
swallowed portion of the dose only negligibly contributes to systemic
exposure.DistributionTiotropiumThe drug has a plasma protein binding of 72% and shows a volume
of distribution of 32 L/kg. Local concentrations in the lung are not
known, but the mode of administration suggests substantially higher
concentrations in the lung. Studies in rats have shown that tiotropium
does not penetrate the blood-brain barrier.OlodaterolOlodaterol
exhibits multi-compartmental disposition kinetics after inhalation
as well as after intravenous administration. The volume of distribution
is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins
is independent of concentration and is approximately 60%. EliminationMetabolismTiotropiumThe extent of metabolism is small. This is evident from
a urinary excretion of 74% of unchanged substance after an intravenous
dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically
cleaved to the alcohol N-methylscopine and dithienylglycolic acid,
both not binding to muscarinic receptors.In vitro experiments with
human liver microsomes and human hepatocytes suggest that a fraction
of the administered dose (74% of an intravenous dose is excreted unchanged
in the urine, leaving 25% for metabolism) is metabolized by cytochrome
P450-dependent oxidation and subsequent glutathione conjugation to
a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited
by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole,
and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic
pathway that is responsible for the elimination of a small part of
the administered dose. In vitro studies using human
liver microsomes showed that tiotropium in supra-therapeutic concentrations
does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.OlodaterolOlodaterol is substantially metabolized by direct glucuronidation
and by O-demethylation at the methoxy moiety followed by conjugation.
Of the six metabolites identified, only the unconjugated demethylation
product binds to beta2-receptors. This metabolite,
however, is not detectable in plasma after chronic inhalation of the
recommended therapeutic dose.Cytochrome P450 isozymes CYP2C9 and CYP2C8,
with negligible contribution of CYP3A4, are involved in the O-demethylation
of olodaterol, while uridine diphosphate glycosyl transferase isoforms
UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation
of olodaterol glucuronides.ExcretionTiotropiumThe terminal half-life of tiotropium
in COPD patients following once daily inhalation of 5 mcg tiotropium
was approximately 25 hours. Total clearance was 880 mL/min after an
intravenous dose in young healthy volunteers. Intravenously administered
tiotropium bromide is mainly excreted unchanged in urine (74%). After
inhalation of the solution by patients with COPD, urinary excretion
is 18.6% (0.932 mcg) of the dose, the remainder being mainly non-absorbed
drug in the gut that is eliminated via the feces. The renal clearance
of tiotropium exceeds the creatinine clearance, indicating secretion
into the urine. After chronic once-daily inhalation by COPD patients,
pharmacokinetic steady state was reached by day 7 with no accumulation
thereafter.OlodaterolTotal clearance of olodaterol in healthy
volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal
half-life following intravenous administration is 22 hours. The terminal
half-life following inhalation in contrast is about 45 hours, indicating
that the latter is determined by absorption rather than by elimination
processes. However, the effective half-life at daily dose of 5 mcg
calculated from Cmax from COPD patients is
7.5 hours.Following
intravenous administration of [14C]-labeled olodaterol, 38% of the
radioactive dose was recovered in the urine and 53% was recovered
in feces. The amount of unchanged olodaterol recovered in the urine
after intravenous administration was 19%. Following oral administration,
only 9% of olodaterol and/or its metabolites was recovered in urine,
while the major portion was recovered in feces (84%). More than 90%
of the dose was excreted within 6 and 5 days following intravenous
and oral administration, respectively. Following inhalation, excretion
of unchanged olodaterol in urine within the dosing interval in healthy
volunteers at steady state accounted for 5% to 7% of the dose. Drug InteractionsSTIOLTO RESPIMATPharmacokinetic
drug interaction studies with STIOLTO RESPIMAT have not been performed;
however, such studies have been conducted with individual components
tiotropium and olodaterol.When tiotropium and olodaterol were administered
in combination by the inhaled route, the pharmacokinetic parameters
for each component were similar to those observed when each active
substance was administered separately.TiotropiumAn
interaction study with tiotropium (14.4 mcg intravenous infusion over
15 minutes) and cimetidine 400 mg three times daily or ranitidine
300 mg once-daily was conducted. Concomitant administration of cimetidine
with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant
change in the Cmax and amount excreted in urine
over 96 hours. Co-administration of tiotropium with ranitidine did
not affect the pharmacokinetics of tiotropium.Common concomitant medications (long-acting
beta2-adrenergic agonists (LABA), inhaled corticosterioids
(ICS)) used by patients with COPD were not found to alter the exposure
to tiotropium.OlodaterolDrug-drug interaction studies were
carried out using fluconazole as a model inhibitor of CYP 2C9 and
ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9) inhibitor.Fluconazole: Co-administration of 400 mg fluconazole once a day for 14 days
had no relevant effect on systemic exposure to olodaterol.Ketoconazole: Co-administration of 400 mg
ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.Tiotropium: Co-administration of tiotropium
bromide, delivered as a fixed-dose combination with olodaterol, for
21 days had no relevant effect on systemic exposure to olodaterol,
and vice versa.Specific PopulationsOlodaterolA pharmacokinetic meta-analysis showed that no dose adjustment
is necessary based on the effect of age, gender, and weight on systemic
exposure in COPD patients after inhalation of olodaterol.Geriatric PatientsTiotropiumAs expected for
all predominantly renally excreted drugs, advancing age was associated
with a decrease of tiotropium renal clearance (347 mL/min in COPD
patients <65 years to 275 mL/min in COPD patients ≥65 years). This
did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values. Renal ImpairmentTiotropiumFollowing inhaled administration
of therapeutic doses of tiotropium to steady-state to patients with
COPD, mild renal impairment (creatinine clearance 60 - <90 mL/min)
resulted in 23% higher AUC0-6,ss and 17% higher
Cmax,ss values. Moderate renal impairment
(creatinine clearance 30 - <60 mL/min) resulted in 57% higher AUC0-6,ss and 31% higher Cmax,ss values
compared to COPD patients with normal renal function (creatinine clearance >90 mL/min). In COPD patients with severe renal impairment
(CLCR <30 mL/min), a single intravenous administration of tiotropium
bromide resulted in 94% higher AUC0-4 and 52%
higher Cmax compared to COPD patients with
normal renal function.OlodaterolOlodaterol levels were increased
by approximately 40% in subjects with severe renal impairment. A study
in subjects with mild and moderate renal impairment was not performed.Hepatic ImpairmentTiotropiumThe effects of
hepatic impairment on the pharmacokinetics of tiotropium were not
studied.OlodaterolSubjects with mild and moderate hepatic impairment showed
no changes in Cmax or AUC, nor did protein
binding differ between mild and moderate hepatically impaired subjects
and their healthy controls. A study in subjects with severe hepatic
impairment was not performed.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

STIOLTO RESPIMATNo studies of the carcinogenicity, in vitro mutagenicity,
or impairment of fertility were conducted with STIOLTO RESPIMAT, however,
studies are available for the individual components, tiotropium and
olodaterol.TiotropiumNo evidence of tumorigenicity was
observed in a 104-week inhalation study in rats at tiotropium doses
up to 59 mcg/kg/day, in an 83-week inhalation study in female mice
at doses up to 145 mcg/kg/day, and in a 101-week inhalation study
in male mice at doses up to 2 mcg/kg/day. These doses correspond to
approximately 30, 40, and 0.5 times the recommended human daily inhalation
dose (RHDID) on a mcg/m2 basis, respectively.Tiotropium bromide demonstrated
no evidence of mutagenicity or clastogenicity in the following assays:
the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis
assay, the chromosomal aberration assay in human lymphocytes in vitro, the mouse micronucleus assay in vivo, and the unscheduled DNA synthesis assay in primary rat hepatocytes in vitro.In rats, decreases in the number of corpora lutea and the percentage
of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day
or greater (approximately 35 times the RHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day
(approximately 4 times than the RHDID on a mcg/m2 basis). The fertility index; however, was not affected at inhalation
doses up to 1689 mg/kg/day (approximately 760 times the RHDID on a
mcg/m2 basis).OlodaterolTwo-year inhalation studies were conducted in rats and mice to assess
the carcinogenic potential of olodaterol. Lifetime treatment of female
rats induced leiomyomas of the mesovarium at doses of 25.8 and 270
mcg/kg/day (approximately 18- and 198-fold, respectively, the RHDID
on an AUC basis). No tumor findings were observed in male rats at
doses up to 270 mcg/kg/day (approximately 230-fold the RHDID on an
AUC basis). Lifetime treatment of female mice induced leiomyomas and
leiomyosarcomas of the uterus at doses ≥76.9 mcg/kg/day (approximately
106-fold the RHDID on an AUC basis). No tumor findings were observed
in male mice at doses up to 255 mcg/kg/day (approximately 455-fold
the RHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas
of the female rodent reproductive tract have been similarly demonstrated
with other beta2-adrenergic agonist drugs.
The relevance of these findings to human use is unknown.Olodaterol was not mutagenic
in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of
micronuclei in rats after intravenous doses. The increased frequency
of micronuclei was likely related to drug enhanced (compensatory)
erythropoiesis. The mechanism for induction of micronuclei formation
is likely not relevant at clinical exposures.Olodaterol did not impair male or female
fertility in rats at inhalation doses up to 3068 mcg/kg/day (approximately
2322 times the RHDID on an AUC basis).

14  Clinical Studies

The
safety and efficacy of STIOLTO RESPIMAT were evaluated in a clinical
development program that included three dose ranging trials, two active-controlled
trials, three active- and placebo-controlled trials, and one placebo-controlled
trial. The efficacy of STIOLTO RESPIMAT is based primarily on two
4-week dose-ranging trials in 592 COPD patients and two confirmatory
active-controlled 52-week trials (Trials 1 and 2) in 5162 COPD patients.Dose-Ranging TrialsDose selection for STIOLTO RESPIMAT was primarily based
on trials for the individual components, tiotropium bromide and olodaterol.Dose selection was also supported
by two randomized, double-blind, active-controlled, 4-week trials.
In one trial in 232 patients with COPD, three tiotropium doses (1.25,
2.5, and 5 mcg) were given in combination with olodaterol 5 or 10
mcg and were evaluated compared to olodaterol monotherapy. Results
demonstrated improvement in trough FEV1 for
the combination when compared to olodaterol alone. The difference
in trough FEV1 for the tiotropium bromide/olodaterol
doses of 1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg
were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084
L (0.046, 0.122), respectively. In the second trial in 360 patients
with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in
combination with tiotropium 5 mcg and were evaluated compared to tiotropium
monotherapy. The difference in trough FEV1 for
the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily
from tiotropium 5 mcg were 0.024 L (95% CI -0.029, 0.076), 0.033 L
(-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively. Results
of these trials supported the evaluation of once-daily doses of tiotropium
bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.Confirmatory TrialsA total of 5162 COPD patients (1029 receiving STIOLTO
RESPIMAT, 1038 receiving olodaterol 5 mcg, and 1033 receiving tiotropium
bromide 5 mcg) were studied in two confirmatory trials of STIOLTO
RESPIMAT. Trials 1 and 2 were 52-week, replicate, randomized, double-blind,
active controlled, parallel group trials that compared STIOLTO RESPIMAT
to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products
were administered via the RESPIMAT inhaler.The trials enrolled patients 40 years of age
or older with a clinical diagnosis of COPD, a smoking history of more
than 10 pack-years, and moderate to very severe pulmonary impairment
(post-bronchodilator FEV1 less than 80% predicted
normal [GOLD Stage 2-4]; post-bronchodilator FEV1 to FVC ratio of less than 70%). All treatments were administered
once daily in the morning. The primary endpoints were change from
baseline in FEV1 AUC0-3hr and trough FEV1 after 24-weeks of treatment.The majority of the 5162 patients
were male (73%), white (71%) or Asian (25%), with a mean age of 64.0
years. Mean post-bronchodilator FEV1 was 1.37
L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). Mean beta2-agonist responsiveness was 16.6% of baseline (0.171
L). Pulmonary medications allowed as concomitant therapy included
inhaled steroids [47%] and xanthines [10%].In both Trials 1 and 2, STIOLTO RESPIMAT
demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg
(Table 2). The increased bronchodilator effects of STIOLTO RESPIMAT
compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained
throughout the 52-week treatment period. STIOLTO RESPIMAT displayed
a mean increase in FEV1 from baseline of 0.137
L (range: 0.133-0.140 L) within 5 minutes after the first dose. Patients
treated with STIOLTO RESPIMAT used less rescue medication compared
to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.Table 2 FEV1 AUC0-3hr and Trough FEV1 response for STIOLTO RESPIMAT
compared to tiotropium 5 mcg and olodaterol 5 mcg after 24 weeks (primary
endpoints; Trials 1 and 2) Pre-treatment baseline FEV1: Trial 1=1.16 L; Trial 2=1.15 Lp≤0.0001 for all comparisons between STIOLTO RESPIMAT
and the monotherapies. Trial 1Trial 2 nMean (L)Difference (L) (95% CI)nMean (L)Difference (L) (95% CI)FEV1 AUC0-3hr response      STIOLTO
RESPIMAT 5220.256-5020.268-Tiotropium
5 mcg5260.1390.117 (0.094,
0.140)5000.1650.103 (0.078,
0.127) Olodaterol
5 mcg5250.1330.123 (0.100,
0.146) 5070.1360.132 (0.108,
0.157)Trough FEV1 response       STIOLTO
RESPIMAT 5210.136-4970.145-Tiotropium
5 mcg5200.0650.071 (0.047,
0.094)4980.0960.050 (0.024,
0.075) Olodaterol
5 mcg5190.0540.082 (0.059,
0.106)5030.0570.088 (0.063,
0.113) For the subset of patients
(n=521) who completed extended lung function measurements up to 12
hours post-dose, STIOLTO RESPIMAT showed a significantly greater FEV1 response compared to tiotropium 5 mcg and olodaterol
5 mcg over the full 24-hour dosing interval. Results from Trial 2
are shown in Figure 1.Figure 1 FEV1 profile for STIOLTO
RESPIMAT, tiotropium 5 mcg and olodaterol 5 mcg over a 24-hour dosing
interval after 24 weeks (12 hr PFT subset from Trial 2)The St. George’s Respiratory Questionnaire
(SGRQ) was assessed in Trials 1 and 2 and in two additional 12-week
placebo-controlled trials.In the first 12-week trial, SGRQ responder
rates at week 12 (defined as an improvement in score of 4 or more
as a threshold) were 53%, 42%, and 31% for STIOLTO RESPIMAT, tiotropium
5mcg, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1,
2.4) and 2.5 (95% CI 1.6, 3.8) for STIOLTO RESPIMAT vs. tiotropium
5mcg and STIOLTO RESPIMAT vs. placebo, respectively. In the second
12-week trial, results were similar with odds ratios of 1.5 (95% CI
1.0, 2.3) and 2.2 (95% CI 1.5, 3.4) for STIOLTO RESPIMAT vs. tiotropium
5mcg and STIOLTO RESPIMAT vs. placebo, respectively. For the 52-week
trials similar responder rates were seen. In Trial 1, the odds ratios
for STIOLTO vs. tiotropium 5mcg and STIOLTO vs. olodaterol 5mcg at
week 24 were 1.6 (95% CI 1.2, 2.0) and 1.9 (95% CI 1.5, 2.4), respectively.
The results were similar in the 52-week Trial 2, with odds ratios
for STIOLTO vs. tiotropium 5mcg and STIOLTO vs. olodaterol 5mcg of
1.3 (95% CI 1.0, 1.7) and 1.5 (95% CI 1.1, 1.9), respectively.

16  How Supplied/Storage And Handling

  • STIOLTO RESPIMAT
  • Inhalation Spray is supplied in a labeled carton containing one STIOLTO
  • RESPIMAT cartridge and one STIOLTO RESPIMAT inhaler.The STIOLTO RESPIMAT cartridge is provided
  • As an aluminum cylinder with a tamper protection seal on the cap.
  • The STIOLTO RESPIMAT cartridge is only intended for use with the STIOLTO
  • RESPIMAT inhaler and should not be interchanged with any other RESPIMAT
  • Device delivered product. The STIOLTO RESPIMAT inhaler is a cylindrical
  • Shaped plastic inhalation device with a gray colored body and a clear
  • Base. The clear base is removed to insert the cartridge. The inhaler
  • Contains a dose indicator. The light green-colored cap and the written
  • Information on the label of the gray inhaler body indicate that it
  • Is labeled for use with the STIOLTO RESPIMAT cartridge.STIOLTO RESPIMAT Inhalation Spray
  • Is available as:STIOLTO RESPIMAT Inhalation Spray: 60 metered actuations
  • (NDC 0597-0155-61)The STIOLTO RESPIMAT cartridge
  • Has a net fill weight of at least 4 grams and when used with the STIOLTO
  • RESPIMAT inhaler, is designed to deliver the labeled number of metered
  • Actuations after preparation for use.When the labeled number of actuations has
  • Been dispensed from the inhaler, the RESPIMAT locking mechanism will
  • Be engaged and no more actuations can be dispensed.After assembly, the STIOLTO RESPIMAT inhaler
  • Should be discarded at the latest 3 months after first use or when
  • The locking mechanism is engaged, whichever comes first. Keep out of reach of children.
  • Do not spray into eyes. StorageStore at 25°C (77°F); excursions
  • Permitted to 15°C to 30°C (59°F to 86oF) [see USP Controlled Room Temperature]. Avoid freezing.

17  Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling
  • (Medication Guide and Instructions for Use).Asthma-Related DeathInform patients that LABA, such as STIOLTO RESPIMAT,
  • Increase the risk of asthma-related death. STIOLTO RESPIMAT is not
  • Indicated for the treatment of asthma.Not for Acute SymptomsSTIOLTO RESPIMAT is not meant to relieve acute asthma
  • Symptoms or exacerbations of COPD and extra doses should not be used
  • For that purpose. Acute symptoms should be treated with an inhaled,
  • Short-acting beta2-agonist such as albuterol.
  • (The healthcare provider should provide the patient with such medication
  • And instruct the patient in how it should be used.)Instruct patients to notify their physician
  • Immediately if they experience any of the following: Worsening of symptomsDecreasing effectiveness of inhaled, short-acting beta2-agonistsNeed for more inhalations than usual of inhaled, short-acting
  • Beta2-agonistsSignificant decrease in lung function as outlined by the
  • PhysicianInstruct patients not to
  • Stop therapy with STIOLTO RESPIMAT without physician/provider guidance
  • Since symptoms may recur after discontinuation.Do Not Use Additional Long-Acting
  • Beta2-AgonistsPatients
  • Who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue
  • The regular use of these products and use them only for the symptomatic
  • Relief of acute symptoms.When patients are prescribed STIOLTO RESPIMAT, other inhaled medications
  • Containing long-acting beta2-agonists should
  • Not be used. Patients should not use more than the recommended once-daily
  • Dose of STIOLTO RESPIMAT. Excessive use of sympathomimetics may cause
  • Significant cardiovascular effects, and may be fatal.Risks Associated with Beta2-Agonist TherapyInform patients
  • Of adverse effects associated with beta2-agonists,
  • Such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.Paradoxical BronchospasmInform patients that STIOLTO RESPIMAT can produce paradoxical
  • Bronchospasm. Advise patients that if paradoxical bronchospasm occurs,
  • Patients should discontinue STIOLTO RESPIMAT.Urinary RetentionDifficulty passing urine and dysuria may be symptoms of new or worsening
  • Prostatic hyperplasia or bladder outlet obstruction. Patients should
  • Be instructed to consult a physician immediately should any of these
  • Signs or symptoms develop.Visual EffectsEye pain or discomfort, blurred vision, visual halos or colored
  • Images in association with red eyes from conjunctival congestion and
  • Corneal edema may be signs of acute narrow-angle glaucoma. Inform
  • Patients to consult a physician immediately should any of these signs
  • And symptoms develop. Advise patients that miotic eye drops alone
  • Are not considered to be effective treatment.Inform patients that care must be taken not
  • To allow the aerosol cloud to enter into the eyes as this may cause
  • Blurring of vision and pupil dilation.Since dizziness and blurred vision may occur
  • With the use of STIOLTO RESPIMAT, caution patients about engaging
  • In activities such as driving a vehicle or operating appliances or
  • Machinery.Instructions for Administering STIOLTO RESPIMATIt is important for patients to understand how to correctly administer
  • STIOLTO RESPIMAT inhalation spray using the STIOLTO RESPIMAT inhaler.
  • Instruct patients that STIOLTO RESPIMAT inhalation spray should only
  • Be administered via the STIOLTO RESPIMAT inhaler and the STIOLTO RESPIMAT
  • Inhaler should not be used for administering other medications.Instruct patients that priming
  • STIOLTO RESPIMAT is essential to ensure appropriate content of the
  • Medication in each actuation.When using the unit for the first time, the
  • STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler
  • And the unit is primed. STIOLTO RESPIMAT patients are to actuate the
  • Inhaler toward the ground until an aerosol cloud is visible and then
  • To repeat the process three more times. The unit is then considered
  • Primed and ready for use. If not used for more than 3 days, patients
  • Are to actuate the inhaler once to prepare the inhaler for use. If
  • Not used for more than 21 days, patients are to actuate the inhaler
  • Until an aerosol cloud is visible and then repeat the process three
  • More times to prepare the inhaler for use.Distributed by:Boehringer Ingelheim
  • Pharmaceuticals, Inc.Ridgefield, CT 06877 USASTIOLTO® and RESPIMAT® are registered trademarks
  • And are used under license from Boehringer Ingelheim International
  • GmbHCopyright © 2016
  • Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDIT6053GF142016305630-04

Spl Medguide

  • Medication GuideSTIOLTO® RESPIMAT® (sti-OL-to– RES peh
  • Mat)(tiotropium bromide and olodaterol) Inhalation SprayRead the Medication Guide that
  • Comes with STIOLTO RESPIMAT 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 STIOLTO RESPIMAT?STIOLTO
  • RESPIMAT has been approved for chronic obstructive pulmonary disease
  • (COPD) only.STIOLTO RESPIMAT is not to be
  • Used in asthma.STIOLTO RESPIMAT can cause serious side effects, including:People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines, such as olodaterol
  • (one of the medicines in STIOLTO RESPIMAT), have an increased risk
  • Of death from asthma problems.It is not known if LABA medicines, such as olodaterol
  • (one of the medicines in STIOLTO RESPIMAT), increase the risk of death
  • In people with COPD.Get emergency medical care if:breathing problems worsen quicklyyou use your rescue inhaler medicine, but it does not relieve
  • Your breathing problemsWhat is STIOLTO RESPIMAT?STIOLTO RESPIMAT contains the anticholinergic tiotropium,
  • And the long-acting beta2-adrenergic agonist
  • (LABA), olodaterol.STIOLTO RESPIMAT is used long term, 2 puffs once each day, in controlling
  • Symptoms of COPD in adults with COPD.Anticholinergic and LABA medicines help the
  • Muscles around the airways in your lungs stay relaxed to prevent symptoms,
  • Such as wheezing, cough, chest tightness, and shortness of breath.STIOLTO RESPIMAT is not
  • For use to treat sudden symptoms of COPD. Always have a rescue
  • Medicine with you to treat sudden symptoms. If you do not have a rescue
  • Inhaler, contact your healthcare provider to have one prescribed for
  • You.It is not
  • Known if STIOLTO RESPIMAT is safe and effective in people with asthma.STIOLTO RESPIMAT
  • Should not be used in children. It is not known if STIOLTO RESPIMAT
  • Is safe and effective in children.Who should not use STIOLTO RESPIMAT?Do not use STIOLTO RESPIMAT if:you have asthma.you are allergic to tiotropium, ipratropium, olodaterol,
  • Or any of the ingredients in STIOLTO RESPIMAT. See the end of this
  • Medication Guide for a complete list of ingredients in STIOLTO RESPIMAT.What should I tell
  • My healthcare provider before using STIOLTO RESPIMAT?Tell your healthcare provider about all of your health conditions,
  • Including if you:have heart problemshave high blood pressurehave seizureshave thyroid problemshave diabeteshave eye problems, such as glaucoma. STIOLTO RESPIMAT can
  • Make your glaucoma worse.have prostate or bladder problems, or problems passing urine.
  • STIOLTO RESPIMAT can make these problems worse.have any other medical conditionsare pregnant or planning to become pregnant. It is not known
  • If STIOLTO RESPIMAT can harm your unborn baby.are breastfeeding. It is not known if STIOLTO RESPIMAT passes
  • Into your breast milk and if it can harm your baby.are allergic to STIOLTO RESPIMAT or any of its ingredients,
  • Any other medicines, or food products.Tell your healthcare
  • Provider about all the medicines you take, including prescription
  • And over-the-counter medicines, eye drops, vitamins, and herbal supplements.
  • STIOLTO RESPIMAT and certain other medicines may interact with each
  • Other. This may cause serious side effects.Especially tell your healthcare provider
  • If you take:anticholinergics (including ipratropium, aclidinium, umeclidinium
  • Or another tiotropium-containing product such as SPIRIVA RESPIMAT
  • Or SPIRIVA HANDIHALER)atropineKnow the medicines you
  • Take. Keep a list of your medicines with you to show your healthcare
  • Provider and pharmacist each time you get a new medicine.How should I use STIOLTO
  • RESPIMAT?Read the step-by-step instructions for using STIOLTO RESPIMAT
  • At the end of this Medication Guide.STIOLTO RESPIMAT inhaler has a slow-moving mist that helps
  • You inhale the medicine.Use STIOLTO RESPIMAT exactly as your healthcare provider
  • Tells you to use it.Use 1 dose (2 puffs) of STIOLTO RESPIMAT, 1 time each
  • Day, at the same time of the day.If you miss a dose of STIOLTO RESPIMAT, take it as soon
  • As you remember. Do not take more than 1 dose (2 puffs) in 24 hours.Do not spray STIOLTO RESPIMAT in your eyes.Always use the new STIOLTO RESPIMAT inhaler that is provided
  • With each new prescription.STIOLTO RESPIMAT 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 STIOLTO RESPIMAT 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 STIOLTO RESPIMAT:more often than prescribed for you, orwith other medicines that contain LABA or an anticholinergic
  • For any reason. Ask your healthcare provider or pharmacist if any
  • Of your other medicines are LABA or anticholinergic medicines.Call your healthcare provider or get emergency medical
  • Care right away if:your breathing problems worsen with STIOLTO RESPIMATyou need to use your rescue medicine more often than usualyour rescue inhaler medicine does not work as well for you
  • At relieving your symptomsWhat are the possible
  • Side effects with STIOLTO RESPIMAT?STIOLTO
  • RESPIMAT can cause serious side effects, including:See “What is the most important information I should
  • Know about STIOLTO RESPIMAT?”If your COPD symptoms worsen over time do not increase your
  • Dose of STIOLTO RESPIMAT, instead call your healthcare provider.sudden shortness of breath that may be life-threateningserious 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.heart problems including fast or irregular heartbeat, palpitations,
  • Chest pain, increased blood pressurenew or worsening eye problems including acute narrow-angle
  • Glaucoma. Symptoms of acute narrow-angle glaucoma include eye pain
  • Or discomfort, blurred vision, seeing halos or colored images around
  • Lights, and red eyes. Call your healthcare provider right away if
  • You have any of these symptoms. Use caution as some of these eye problems
  • Can affect your ability to drive and operate appliances and machinery.new or worsening urinary retention. Symptoms of urinary
  • Retention may include difficulty urinating, painful urination, urinating
  • Frequently, or urinating in a weak stream or drips. Call your healthcare
  • Provider right away if you have any of these symptoms.low blood potassium (which may cause symptoms of muscle
  • Spasm, muscle weakness or abnormal heart rhythm)high blood sugarCommon side effects
  • Of STIOLTO RESPIMAT include runny nose, cough, and back pain.Tell your healthcare provider
  • About any side effect that bothers you or that does not go away.These are not all the side effects
  • With STIOLTO RESPIMAT. 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 STIOLTO
  • RESPIMAT?Store STIOLTO RESPIMAT at room temperature 68°F to 77°F
  • (20°C to 25°C).Do not freeze your STIOLTO cartridge or RESPIMAT inhaler.Keep your STIOLTO RESPIMAT and all medicines out of
  • The reach of children.General Information
  • About the safe and effective use of STIOLTO RESPIMATMedicines are sometimes prescribed for purposes other than those
  • Listed in a Medication Guide. Do not use STIOLTO RESPIMAT for a condition
  • For which it was not prescribed. Do not give STIOLTO RESPIMAT to other
  • People, even if they have the same condition. It may harm them.This Medication Guide summarizes
  • The most important information about STIOLTO RESPIMAT. If you would
  • Like more information, talk with your healthcare provider. You can
  • Ask your healthcare provider or pharmacist for information about STIOLTO
  • RESPIMAT that was written for healthcare professionals.For more information about STIOLTO
  • RESPIMAT or a video demonstration on how to use STIOLTO RESPIMAT,
  • Go to www.STIOLTO.com, or scan the code below. You may also call 1-800-542-6257
  • Or (TTY) 1-800-459-9906 for further information about STIOLTO RESPIMAT.What are the ingredients in STIOLTO
  • RESPIMAT?Active ingredients: Tiotropium bromide
  • And olodaterolInactive ingredients: water for injection,
  • Benzalkonium chloride, edetate disodium, and hydrochloric acid

Instructions For Use

  • Instructions for UseSTIOLTO® RESPIMAT® (sti-OL-to- RES peh
  • Mat)(tiotropium bromide and olodaterol)Inhalation
  • SprayFor Oral
  • Inhalation OnlyDo not spray STIOLTO RESPIMAT into your
  • Eyes.Read these
  • Instructions for Use before you start using STIOLTO RESPIMAT and each
  • Time you get a refill. There may be new information. This leaflet
  • Does not take the place of talking to your doctor about your medical
  • Condition or your treatment.You will need to use this inhaler ONCE A
  • DAY, at the same time each day. Each time you use it take TWO PUFFS.Do not turn the clear base
  • Before inserting the cartridge.How to store your
  • STIOLTO RESPIMAT inhalerStore STIOLTO RESPIMAT at room temperature 68°F to 77°F
  • (20°C to 25°C).Do not freeze your STIOLTO RESPIMAT cartridge and inhaler.If STIOLTO RESPIMAT has not been used for more than 3 days,
  • Release 1 puff towards the ground.If STIOLTO RESPIMAT has not been used for more than 21 days,
  • Repeat steps 4 to 6 under the “Prepare for first use” until a mist
  • Is visible. Then repeat steps 4 to 6 three more times.Keep your STIOLTO RESPIMAT cartridge and inhaler out of
  • The reach of children.How to care for
  • Your STIOLTO RESPIMAT inhalerClean the mouthpiece, including the metal
  • Part inside the mouthpiece, with a damp cloth or tissue only, at least
  • Once a week. Any minor discoloration in the mouthpiece does not affect
  • Your STIOLTO RESPIMAT inhaler.When to get a new STIOLTO RESPIMAT
  • InhalerYour inhaler contains 60 puffs (30 doses) if used as indicated
  • (2 puffs once daily). If you have a sample, your inhaler contains
  • 28 puffs (14 doses) if used as indicated (2 puffs once daily).The dose indicator shows approximately how much medicine
  • Is left.When the dose indicator enters the red area of the scale
  • You need to get a refill; there is approximately medicine for 7 days
  • Left (if you have a sample, there is approximately medicine for 3
  • Days left).When the dose indicator reaches the end of the red scale,
  • Your STIOLTO RESPIMAT is empty and automatically locks. At this point,
  • The clear base cannot be turned any further.Three months after insertion of cartridge, throw away the
  • STIOLTO RESPIMAT even if it has not been used, or when the inhaler
  • Is locked, or when it expires, whichever comes first.Prepare for first
  • Use1. Remove
  • Clear baseKeep the cap closed.Press the safety catch while firmly pulling off the clear
  • Base with your other hand. Be careful not to touch the piercing element.Write the discard by date on the label (3 months from the
  • Date the cartridge is inserted).2. Insert
  • CartridgeInsert the narrow end of the cartridge into the inhaler.Place the inhaler on a firm surface and push down firmly
  • Until it clicks into place.3. Replace
  • Clear basePut the clear base back into place until it clicks.Do not remove the clear base or the cartridge after it has
  • Been put together.4. TurnKeep the cap closed.Turn the clear base in the direction of the arrows on the
  • Label until it clicks (half a turn).5. OpenOpen the cap until it snaps fully open.6. PressPoint the inhaler toward the ground.Press the dose-release button.Close the cap.If you do not see a mist, repeat steps 4 to 6 until a mist
  • Is seen.After a mist is seen, repeat steps 4 to 6 three more
  • Times.After complete preparation of your inhaler, it will be ready
  • To deliver the number of puffs on the label.Daily use (TOP)TurnKeep the cap closed.Turn the clear base in the direction of the
  • Arrows on the label until it clicks (half a turn).OpenOpen the cap until it snaps fully open.PressBreathe out slowly and fully.Close your lips around the mouthpiece without covering the
  • Air vents.Point the inhaler to the back of your throat.While taking a slow, deep breath through your mouth, Press the dose-release button and continue to breathe in.Hold your breath for 10 seconds or for as long as comfortable.Repeat Turn, Open, Press (TOP) for a total of 2 puffs.Close the cap until you use your inhaler again.Answers to Common
  • QuestionsIt is difficult to insert the cartridge deep enough:Did
  • You accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button, then insert the cartridge.Did you insert the cartridge
  • With the wide end first? Insert the cartridge with the narrow
  • End first.I cannot press the dose-release button:Did you turn the clear
  • Base? If not, turn the clear base in a continuous movement
  • Until it clicks (half a turn).Is the dose indicator on the STIOLTO
  • RESPIMAT pointing to zero? The STIOLTO RESPIMAT inhaler is
  • Locked after 60 puffs (30 doses). If you have a sample, the STIOLTO
  • RESPIMAT inhaler is locked after 28 puffs (14 doses). Prepare and
  • Use your new STIOLTO RESPIMAT inhaler.I cannot turn the clear
  • Base:Did you turn the clear base already? If the clear base
  • Has already been turned, follow steps “Open” and “Press” under “Daily
  • Use” to get your medicine.Is the dose indicator on the STIOLTO
  • RESPIMAT pointing to zero? The STIOLTO RESPIMAT inhaler is
  • Locked after 60 puffs (30 doses). If you have a sample, the STIOLTO
  • RESPIMAT inhaler is locked after 28 puffs (14 doses). Prepare and
  • Use your new STIOLTO RESPIMAT inhaler.The dose indicator on the
  • STIOLTO RESPIMAT reaches zero too soon:Did you use STIOLTO RESPIMAT
  • As indicated (2 puffs once daily)? STIOLTO RESPIMAT will deliver
  • 60 puffs and last 30 days if used at 2 puffs once daily. If you have
  • A sample, STIOLTO RESPIMAT will deliver 28 puffs and last 14 days
  • If used at 2 puffs once daily.Did you turn the clear base before
  • You inserted the cartridge? The dose indicator counts each
  • Turn of the clear base regardless whether a cartridge has been inserted
  • Or not.Did
  • You spray in the air often to check whether the STIOLTO RESPIMAT is
  • Working? Once you have prepared STIOLTO RESPIMAT, no test-spraying
  • Is required if used daily.Did you insert the cartridge into
  • A used STIOLTO RESPIMAT? Always insert a new cartridge into
  • A NEW STIOLTO RESPIMAT.My STIOLTO RESPIMAT sprays
  • Automatically:Was the cap open when you turned the
  • Clear base? Close the cap, then turn the clear base.Did you press the dose-release
  • Button when turning the clear base? Close the cap, so the dose-release
  • Button is covered, then turn the clear base.Did you stop when turning the clear
  • Base before it clicked? Turn the clear base in a continuous movement until it clicks (half a turn).My STIOLTO
  • RESPIMAT doesn’t spray:Did you insert a cartridge? If not, insert a cartridge.Did you repeat Turn, Open, Press (TOP)
  • Less than three times after inserting the cartridge? Repeat Turn, Open, Press (TOP) three times after inserting the cartridge as shown in
  • Steps 4 to 6 under “Prepare for first use”.Is the dose indicator on the STIOLTO
  • RESPIMAT pointing to 0? You have used up all your medicine
  • And the inhaler is locked.For more information about STIOLTO RESPIMAT
  • Or a video demonstration on how to use STIOLTO RESPIMAT, go to www.stiolto.com, or scan the code below. You may also
  • Call 1-800-542-6257 or (TTY) 1-800-459-9906 for further information
  • About STIOLTO RESPIMAT.This Medication Guide
  • And Instructions for Use has been approved by the U.S. Food and Drug
  • Administration.Distributed
  • By: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877
  • USASPIRIVA®, HANDIHALER®, STIOLTO® and RESPIMAT® are registered
  • Trademarks and are used under license from Boehringer Ingelheim International
  • GmbHCopyright © 2016
  • Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDRevised: June 2016IT6053GF142016305630-04

* Please review the disclaimer below.