Tiotropium and Olodaterol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol Solution, Inhalation:

Stiolto Respimat: Tiotropium 2.5 mcg and olodaterol 2.5 mcg per actuation (4 g) [contains benzalkonium chloride, edetate disodium]

Pharmacology

Mechanism of Action

Tiotropium: Competitively and reversibly inhibits the action of acetylcholine at type 3 muscarinic (M3) receptors in bronchial smooth muscle causing bronchodilation.

Olodaterol: Long acting beta₂-receptor agonist; activates beta₂ airway receptors, resulting in the stimulation of intracellular adenyl cyclase and a subsequent increase in the synthesis of cyclic-3’,5’ adenosine monophosphate (cAMP). Elevated cAMP levels induce bronchodilation by relaxation of airway smooth muscle cells. Has much greater affinity for beta₂-receptors than for beta₁- or beta₃-receptors.

Use: Labeled Indications

COPD: Maintenance treatment of patients with COPD, including chronic bronchitis and/or emphysema.

Contraindications

Hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of the formulation; monotherapy (without use of a concomitant inhaled corticosteroid) in the treatment of asthma.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to atropine.

Documentation of allergenic cross-reactivity for sympathomimetics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

COPD: Oral inhalation: Soft mist inhaler: Two inhalations (tiotropium 2.5 mcg/olodaterol 2.5 mcg per actuation) once daily (maximum: 2 inhalations/day)

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral inhalation: Soft mist inhaler: For oral inhalation only. Administer at the same time each day. Prime inhaler prior to initial use or if not used for >21 days; point inhaler toward ground and actuate until aerosol cloud is seen, then repeat 3 additional times before use. If not used for >3 days (but ≤21 days), actuate once before use. When dose is ready to be administered, breathe in slowly through the mouth and press the dose-release button; continue to breathe in slowly as long as possible, then hold breath for 10 seconds or for as long as comfortable. Repeat for second inhalation.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing. Discard 3 months after cartridge is inserted into inhaler or when the locking mechanism is engaged, whichever comes first.

Drug Interactions

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Anticholinergic Agents: May enhance the anticholinergic effect of Tiotropium. Avoid combination

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Beta2-Agonists (Long-Acting): May enhance the adverse/toxic effect of other Beta2-Agonists (Long-Acting). Avoid combination

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Caffeine and Caffeine Containing Products: May enhance the adverse/toxic effect of Olodaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Olodaterol. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Methacholine: Beta2-Agonists (Long-Acting) may diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta₂ agonists for 36 hours before methacholine use. Consider therapy modification

Methacholine: Long-acting muscarinic antagonists (LAMAs) may diminish the therapeutic effect of Methacholine. Consider therapy modification

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Theophylline Derivatives: May enhance the adverse/toxic effect of Olodaterol. Theophylline Derivatives may enhance the hypokalemic effect of Olodaterol. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Adverse Reactions

>10%:

Respiratory: Nasopharyngitis (12%)

1% to 10%:

Neuromuscular & skeletal: Back pain (4%)

Respiratory: Cough (4%)

≤3%, postmarketing, and/or case reports: Angioedema, arthralgia, atrial fibrillation, blurred vision, bronchospasm, constipation, dehydration, dermal ulcer, dizziness, dysphagia, dysuria, epistaxis, gastroesophageal reflux disease, gingivitis, glaucoma, glossitis, hypersensitivity (including immediate reactions), hypertension, increased intraocular pressure, insomnia, intestinal obstruction (including paralytic ileus), joint swelling, laryngitis, oropharyngeal candidiasis, palpitations, pharyngitis, pruritus, sinusitis, skin infection, skin rash, stomatitis, supraventricular tachycardia, tachycardia, urinary retention, urinary tract infection, urticaria, voice disorder, xeroderma, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: Monotherapy with a long-acting beta-2 agonist (LABA) is contraindicated in the treatment of asthma. In a large, randomized, placebo-controlled US clinical trial (SMART 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone. Current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2018; NIH/NHLBI 2007). In a more recent multicenter, randomized, double-blinded trial, the use of salmeterol and an inhaled corticosteroid (ie, fluticasone) combined in a single inhaler in a large number of children, adolescent, and adult patients with persistent asthma (nonlife-threatening and stable) did not increase the risk of serious asthma-related events compared with fluticasone alone; in addition, patients receiving fluticasone/salmeterol had fewer severe asthma exacerbations compared with patients receiving fluticasone alone (Peters 2016; Stempel 2016a; Stempel 2016b). Tiotropium/olodaterol is not indicated for the treatment of asthma. Available data do not suggest an increased risk of death with use of LABA in patients with chronic obstructive pulmonary disease (COPD).
• Bronchospasm: Paradoxical bronchospasm that may be life-threatening may occur with use of inhaled beta-2 agonists; this should be distinguished from inadequate response. If paradoxical bronchospasm occurs, discontinue use and institute alternative therapy.
• CNS effects: May cause dizziness and blurred vision; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hypersensitivity reactions: Immediate hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, rash, and urticaria may occur; discontinue immediately if signs/symptoms of a hypersensitivity reaction occur.
• Serious effects/fatalities: Do not exceed recommended dose or frequency or use with other medications containing LABAs; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (eg, arrhythmias, coronary insufficiency, hypertension, and hypertrophic obstructive cardiomyopathy); beta-agonists may cause elevation in blood pressure and heart rate. Beta-2 agonists may also produce ECG changes (eg, T-wave flattening, QTc prolongation, ST segment depression).
• Diabetes: Use with caution in patients with diabetes mellitus; beta-2 agonists may increase serum glucose and aggravate preexisting diabetes mellitus and ketoacidosis.
• Glaucoma: Use with caution in patients with narrow angle glaucoma; may increase intraocular pressure.
• Hyperthyroidism: Use with caution in patients with hyperthyroidism; beta-2 agonists may stimulate thyroid activity.
• Hypokalemia: Use with caution in patients with hypokalemia; beta-2 agonists may decrease serum potassium (transient).
• Renal impairment: Use with caution in patients with moderate to severe renal impairment (creatinine clearance of <60 mL/minute); monitor closely for anticholinergic adverse events.
• Seizures: Use with caution in patients with seizure disorders; beta-2 agonists may result in CNS stimulation/excitation.
• Urinary retention: Use with caution in patients with urinary retention. Monitor for signs and symptoms of urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: LABAs, when used as monotherapy, may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials in adolescents do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone.

Other warnings/precautions:

• Appropriate use: Not indicated for the initial (rescue) treatment of acute episodes of bronchospasm or with acutely deteriorating or potentially life-threatening COPD; after initiation of therapy, patients should use short-acting bronchodilators only on an as needed basis for acute symptoms.

Monitoring Parameters

FEV₁, peak flow and/or other pulmonary function tests; anticholinergic adverse reactions (patients with CrCl ≤60 mL/minute); serum potassium; serum glucose; blood pressure, heart rate; CNS stimulation; signs and symptoms of glaucoma; hypersensitivity reactions; urinary retention.

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Beta-agonists have the potential to affect uterine contractility if administered during labor. See individual monographs.

Patient Education

What is this drug used for?

• It is used to treat COPD (chronic obstructive pulmonary disease).
• This drug is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor.

Frequently reported side effects of this drug

• Back pain
• Runny nose

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Anxiety
• Severe headache
• Severe dizziness
• Passing out
• Tremors
• Vision changes
• Severe eye pain
• Severe eye irritation
• Seeing halos or bright colors around lights
• Eye redness
• Difficult urination
• Painful urination
• Unable to pass urine
• Passing a lot of urine
• Difficulty breathing
• Wheezing
• Cough
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.