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Tiotropium and Olodaterol

Pronunciation

(ty oh TRO pee um & oh loe DA ter ol)

Index Terms

  • Olodaterol and Tiotropium
  • Tiotropium Br/Olodaterol HCl
  • Tiotropium Bromide 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]

Brand Names: U.S.

  • Stiolto Respimat

Pharmacologic Category

  • Anticholinergic Agent
  • Anticholinergic Agent, Long-Acting
  • Beta2 Agonist
  • Beta2 Agonist, Long-Acting

Pharmacology

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

Chronic obstructive pulmonary disease: Maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Limitations of use: Not indicated to treat acute deteriorations of COPD; not indicated to treat asthma (safety and effectiveness in asthma have not been established)

Contraindications

Hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of the formulation; use in the treatment of asthma without a concomitant long-term asthma control medication.

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.

Dosing: Adult

COPD: Oral inhalation: Two inhalations once daily (maximum: 2 inhalations per day)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl ≤60 mL/minute: No dosage adjustment necessary; monitor closely for anticholinergic adverse effects.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Administration

For oral inhalation only. 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

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

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

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

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

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

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: 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. Avoid combination

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

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

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

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

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

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

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

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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. Avoid combination

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. 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

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

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

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

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% (Limited to important or life-threatening): Angioedema, atrial fibrillation, bronchospasm, constipation, dehydration, dermal ulcer, 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, sinusitis, skin infection, skin rash, stomatitis, supraventricular tachycardia, tachycardia, urinary retention, urinary tract infection, voice disorder, xeroderma

ALERT: U.S. Boxed Warning

Asthma-related death:

Long-acting beta2-adrenergic agonists (LABA) such as olodaterol, one of the active ingredients in tiotropium/olodaterol, 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 of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including olodaterol. The safety and efficacy of tiotropium/olodaterol in patients with asthma have not been established. Tiotropium/olodaterol is not indicated for the treatment of asthma.

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-agonists (LABAs) increase the risk of asthma-related deaths. The safety and efficacy of olodaterol in the treatment of asthma have not been established. 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. Tiotropium/olodaterol is not indicated for the treatment of asthma. It is unknown if olodaterol increases asthma-related deaths. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use; however, current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2015; 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 adolescent and adult patients with persistent asthma (non-life 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 (Stempel 2016). No data exist associating LABA use with an increased risk of death in patients with COPD.

• Bronchospasm: Paradoxical bronchospasm may occur with use of inhaled agents; distinguish from inadequate response, discontinue medication immediately, 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 urticaria, angioedema, itching, rash, bronchospasm, or anaphylaxis, have been reported. Discontinue immediately if signs/symptoms occur. Use with caution in patients with a history of hypersensitivity to atropine or its derivatives.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disorders, especially arrhythmias, coronary insufficiency, hypertension, and hypertrophic obstructive cardiomyopathy; beta-agonists may cause elevation in blood pressure and heart rate. Beta2-agonists may also produce electrocardiogram (ECG) changes (eg, T-wave flattening, QTc prolongation, ST segment depression).

• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may increase serum glucose.

• Glaucoma: Tiotropium may worsen symptoms of narrow-angle glaucoma; use with caution.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; beta2-agonists may stimulate thyroid activity.

• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.

• Prostatic hyperplasia/bladder neck obstruction: Tiotropium may worsen the symptoms of prostatic hyperplasia and/or bladder neck obstruction; use with caution.

• Renal impairment: Use with caution in patients with moderate to severe renal impairment; monitor closely for anticholinergic adverse events.

• Seizure disorders: Use with caution in patients with seizure disorders; beta2-agonists may result in CNS stimulation/excitation.

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.

• LABA: Do not use with other long-acting beta2-agonists; deaths and significant cardiovascular effects have been reported with excessive sympathomimetic use.

Other warnings/precautions:

• Appropriate use: COPD: Do not use for acute bronchospastic episodes of COPD; always prescribe with an inhaled short-acting beta2-agonist to treat acute symptoms. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Do not increase the dose or frequency beyond what is recommended.

Monitoring Parameters

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

Monitor for increased use of short-acting beta2-agonist inhalers (may be marker of a deteriorating condition).

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain or rhinorrhea. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, anxiety, severe headache, severe dizziness, tremors, sudden vision changes, severe eye pain, severe eye irritation, urinary retention, pain with urination, polyuria, difficulty breathing, wheezing, or cough (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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