What is Stiolto Respimat (tiotropium bromide and olodaterol)?

Stiolto Respimat (tiotropium bromide and olodaterol) is a combination of an anticholinergic and a long-acting beta2-adrenergic agonist (LABA) used to treat chronic obstructive pulmonary disease (COPD). 

Tiotropium bromide is an inhaled bronchodilator that enlarges (dilates) airways in the lungs and is used to treat COPD. Tiotropium blocks the effect of acetylcholine, a chemical that nerves use to communicate with muscle cells, on airways. In people with chronic COPD, cholinergic nerves going to the lungs cause narrowing of the airways by stimulating muscles surrounding the airways to contract. 

The anticholinergic effect of tiotropium blocks the effect of cholinergic nerves, causing the muscles to relax and airways to dilate. Olodaterol also is an inhaled bronchodilator that relaxes lung airways, improving breathing in people with COPD. Combining two bronchodilators with different mechanisms of action improves breathing more than either drug alone. 

Common side effects of Stiolto Respimat include:

Other side effects of Stiolto Respimat include:

Serious side effects of Stiolto Respimat include:

  • worsening of COPD and pneumonia, and
  • increased risk of asthma-related death.

Drug interactions of Stiolto Respimat include other drugs that affect blood pressure and heart rate, and have similar effects as epinephrine and norepinephrine, which increase side effects of Stiolto Respimat.

Combining Stiolto Respimat with steroids, diuretics, or xanthines increases the risk of low blood potassium (hypokalemia).

Stiolto Respimat should not be used with monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, or other drugs that affect heart rhythm because this may increase the risk of abnormal heartbeats.

Beta-blockers may block the effects of olodaterol and may produce bronchospasms in people with COPD.

Anticholinergic drugs add to the anticholinergic effects of tiotropium, leading to increased side effects. Ketoconazole and other drugs that reduce the activity of certain liver enzymes may increase blood levels of olodaterol.

The safety of Stiolto Respimat or any of its components in pregnant women has not been adequately evaluated. Use of Stiolto Respimat or its components in nursing mothers has not been evaluated. Consult your doctor before breastfeeding.

What are the important side effects of Stiolto Respimat (tiotropium bromide and olodaterol)?

Common side effects of Stiolto Respimat are:

It also causes:

In clinical trials the most frequent serious adverse effects reported were worsening of COPD and pneumonia.

Long-acting beta2-adrenergic agonists such as olodaterol, one of the active ingredients in Stiolto Respimat, increases the risk of asthma-related death.

Stiolto Respimat (tiotropium bromide and olodaterol) side effects list for healthcare professionals

LABA, such as olodaterol, one of the active components in Stiolto Respimat, as monotherapy (without an inhaled corticosteroid) for asthma, increase the risk of asthma-related events. Stiolto Respimat is not indicated for the treatment of asthma.

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

  • Immediate hypersensitivity reactions
  • Paradoxical bronchospasm
  • Worsening of narrow-angle glaucoma
  • Worsening of urinary retention

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 (Trials 1 and 2). 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

COPD Exacerbation Reduction Trial

In a one year trial (Trial 5) of 7880 patients to compare rates of COPD exacerbations, 3939 patients were treated with Stiolto Respimat and 3941 patients were treated with tiotropium 5 mcg inhalation spray. The safety profile of Stiolto Respimat was similar to that of tiotropium 5 mcg inhalation spray and consistent with that documented in the Stiolto Respimat primary safety database.

What drugs interact with Stiolto Respimat (tiotropium bromide and olodaterol)?

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.

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.

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.

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.

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.

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.

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. 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.

Summary

Stiolto Respimat (tiotropium bromide and olodaterol) is a combination of an anticholinergic and a long-acting beta2-adrenergic agonist (LABA) used to treat chronic obstructive pulmonary disease (COPD). Common side effects of Stiolto Respimat include cough, back pain, and stuffy nose. Other side effects of Stiolto Respimat include heart palpitations, fast heart rate, elevated blood pressure, tremors, nervousness, and headache. The safety of Stiolto Respimat or any of its components in pregnant or breastfeeding women has not been adequately evaluated.

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Medically Reviewed on 5/15/2020
References
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Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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