Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 27 February 2017

Indication(s)

1 INDICATIONS AND USAGE STIOLTO RESPIMAT is a combination of tiotropium, an anticholinergic and olodaterol, a long-acting beta2-adrenergic agonist (LABA) indicated for: The long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) (1.1) Important limitations: STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of COPD. (1.2) STIOLTO RESPIMAT is NOT indicated to treat asthma.

(1.2) 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.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD)

View highlights from recent congresses presented in new expert videos with leading physicians.

+ 7 more

Cystic Fibrosis Knowledge Centre

Cystic Fibrosis Knowledge Centre

View disease awareness information, treatment options and European Cystic Fibrosis Society best practice guidelines.

Allergic Rhinitis

Allergic Rhinitis

Allergic rhinitis causes great strain on the workforce. Help to reduce sick days and improve productivity with appropriate treatment options.

+ 4 more

Load more

Related Content

Advisory information

contraindications

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.

All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication.

(4) STIOLTO RESPIMAT is not indicated for the treatment of asthma.

(1.2) Hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product.

(4)

Adverse reactions

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)] The most common adverse reactions (>3 % incidence and more than an active control) were nasopharyngitis, cough, and back pain.

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 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 can not 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 older Treatment STIOLTO RESPIMAT (once daily) Tiotropium (5 mcg once daily) Olodaterol (5 mcg once daily) Body system (adverse drug reaction) n=1029 n (%) n=1033 n (%) n=1038 n (%) Infections and infestations Nasopharyngitis 128 (12.4) 121 (11.7) 131 (12.6) Respiratory, thoracic

and mediastinal disorders Cough 40 (3.9) 45 (4.4) 31 (3.0) Musculoskeletal and connective tissue disorders Back Pain 37 (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: dehydration Nervous system disorders: dizziness, insomnia Eye disorders: glaucoma, intraocular pressure increased, vision blurred Cardiac/vascular disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis Gastrointestinal disorders: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including ileus paralytic Skin 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

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION For oral inhalation only.

Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day.

(2) 2.1 Recommended Dosage 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)].

Use in special populations

8 USE IN SPECIFIC POPULATIONS Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects.

(2, 8.7) 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.

Tiotropium No 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).

Olodaterol Olodaterol 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)].

Pregnancy and lactation

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.

Interactions

7 DRUG INTERACTIONS Other adrenergic drugs may potentiate effect.

Use with caution.

(5.3, 7.1) Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes.

Use with caution.

(7.2, 7.3) MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate effect on cardiovascular system.

Use with extreme caution.

(7.4) Beta-blockers may decrease effectiveness.

Use with caution and only when medically necessary.

(7.5) Anticholinergics: May interact additively with concomitantly used anticholinergic medications.

Avoid administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs.

(7.6) 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.

More information

Category Value
Authorisation number NDA206756
Orphan designation No
Product NDC 0597-0155
Date Last Revised 22-06-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1651266
Marketing authorisation holder Boehringer Ingelheim Pharmaceuticals Inc.
Warnings

WARNING:

ASTHMA-RELATED DEATH 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)].

WARNING:

ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning.

Long-acting beta2-adrenergic agonists (LABA) such as olodaterol, one of the active ingredients in

STIOLTO RESPIMAT, 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) This finding of an increased risk of asthma-related death with salmeterol is considered a class effect of 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.

(4, 5.1)