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Olodaterol Hydrochloride

Class: Selective beta-2-Adrenergic Agonists
VA Class: RE102
Chemical Name: 6 - Hydroxy - 8 - [(1R) - 1 - hydroxy - 2 - [[2 - (4 - methoxyphenyl) - 1,1 - dimethylethyl] - amino]ethyl] - 2H - 1,4 - benzoxazin - 3(4H) - one hydrochloride
Molecular Formula: C21H27ClN2O5
CAS Number: 869477-96-3
Brands: Stiolto Respimat (combination), Striverdi Respimat

Warning(s)

  • Increased risk of asthma-related death with long-acting β2-adrenergic agonists.1 8 9 12 (See Asthma-related Death under Cautions.)

  • Increased risk of asthma-related death considered class effect of long-acting β2-adrenergic agonists, including olodaterol.1 12

  • Safety and efficacy of olodaterol in patients with asthma not established; olodaterol not indicated for treatment of asthma.1 12

Introduction

Bronchodilator; a relatively selective, long-acting β2-adrenergic agonist.1 2 3 4 5 7 11 12

Uses for Olodaterol Hydrochloride

Bronchospasm in COPD

Olodaterol alone or in fixed combination with tiotropium used for long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.1 2 3 4 11 12 13

Not indicated for the treatment of acute bronchospasm (i.e., as rescue therapy for treatment of acute episodes of bronchospasm).1 12

Other Uses

Not indicated for treatment of asthma; safety and efficacy in asthma not established.1 12

Olodaterol Hydrochloride Dosage and Administration

General

  • When initiating olodaterol alone or in fixed combination with tiotropium, discontinue regular use of short-acting inhaled β2-agonists; use such agents only for symptomatic relief of acute respiratory symptoms.1 12

  • Failure to respond to a previously effective dosage may indicate deterioration of COPD that requires immediate reevaluation.1 12 Extra or increased dosages of olodaterol not recommended.1 12 (See Deterioration of Disease and Acute Episodes under Cautions.)

Administration

Administer olodaterol alone by oral inhalation using a specific inhaler (Striverdi Respimat) that delivers a metered-dose spray.1

Administer olodaterol/tiotropium fixed combination by oral inhalation using a specific inhaler (Stiolto Respimat) that delivers a metered-dose spray.12

Both inhalers deliver the drugs in an aqueous solution and mechanically produce a fine aerosol mist from the orally inhaled solution.1 12 14

Administer once daily at the same time every day.1 12

Oral Inhalation

Before first use of either Striverdi Respimat or Stiolto Respimat, place inhaler cartridge into inhaler.1 12 Consult the manufacturer's prescribing information for detailed information on inhaler preparation.1 12 Write discard date (3 months after cartridge is inserted into inhaler) on inhaler label.1 12

Prime inhaler before first use by turning clear base in direction of black arrows on label until click is heard (one-half turn) with inhaler upright and cap closed.1 12 Flip cap until it fully snaps open, then point inhaler away from face, press dose release button, then close cap.1 12

Repeat these steps until spray is visible, then for 3 additional times.1 12 Repeat initial actuation step of priming process (without 3 additional repetitions) after periods of nonuse (i.e., for >3 days).1 12 If inhaler is not used for >21 days, repeat entire priming process.1 12

To administer a dose, hold inhaler upright with cap closed; turn clear base in direction of black arrows on label until click is heard (one-half turn).1 12 Flip cap until it snaps fully open.1 12

Before inhaling dose, exhale slowly and completely.1 12 Close lips around end of mouthpiece without covering air vents.1 12 Pointing inhaler toward back of throat, press dose release button while taking a slow, deep inhalation through the mouth, continuing to inhale for at least as long as spray duration (i.e., 1.5 seconds).1 12 Hold the breath for 10 seconds (or as long as comfortable).1 12 Repeat procedure once more to administer a full dose (2 inhalations), then close cap.1 12

Using only a damp tissue or cloth, clean mouthpiece of the inhaler, including metal part inside, at least once weekly.1 12 Outside of inhaler can be wiped with a damp cloth.1 12 Inhaler function not affected by minor mouthpiece discoloration.1 12

Dosage

Available as olodaterol hydrochloride; dosage expressed in terms of olodaterol.1

Each actuation of the Striverdi Respimat inhaler delivers 2.7 mcg of olodaterol hydrochloride (equivalent to 2.5 mcg of olodaterol).1

Each actuation of the Stiolto Respimat inhaler delivers 2.7 mcg of olodaterol hydrochloride (equivalent to 2.5 mcg of olodaterol) and 3.1 mcg of tiotropium bromide monohydrate (equivalent to 2.5 mcg of tiotropium) per metered spray.12

Precise amount of drug delivered to lungs depends on factors (e.g., patient's coordination between actuation of the inhaler and inspiration through the delivery system).1 12 Respimat inhaler mechanically releases dose; delivered dose not dependent on patient's inspiratory effort.7 14

Commercially available inhaler delivers 60 metered sprays (or 28 metered sprays from the institutional package) equivalent to 30 or 14 doses (2 actuations per dose) of the drug, respectively.1 12

Adults

COPD
Oral Inhalation

Olodaterol: 5 mcg (2 inhalations) once daily.1

Olodaterol/tiotropium fixed-combination therapy: 5 mcg of olodaterol and 5 mcg of tiotropium (2 inhalations) once daily.12

Prescribing Limits

Adults

COPD
Oral Inhalation

Olodaterol: Maximum 5 mcg (2 inhalations) once every 24 hours.1

Olodaterol/tiotropium fixed-combination therapy: Maximum 5 mcg of olodaterol and 5 mcg of tiotropium (2 inhalations) once every 24 hours.12

Special Populations

Hepatic Impairment

Olodaterol or olodaterol/tiotropium fixed-combination therapy: No dosage adjustment required in patients with mild or moderate hepatic impairment; not studied in patients with severe hepatic impairment.1 12

Renal Impairment

Olodaterol: No dosage adjustment required.1

Olodaterol/tiotropium fixed-combination therapy: No dosage adjustment required, but monitor patients with moderate to severe renal impairment for anticholinergic effects.12 (See Renal Impairment under Cautions.)

Geriatric Patients

Olodaterol or olodaterol/tiotropium fixed-combination therapy: No dosage adjustment required.1 12

Cautions for Olodaterol Hydrochloride

Contraindications

  • All long-acting β2-adrenergic agonists, including olodaterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy; olodaterol not indicated for treatment of asthma.1 12 (See Asthma-related Death under Cautions.)

  • Known hypersensitivity to olodaterol or any ingredient in the formulation.12

Warnings/Precautions

Warnings

Use of Fixed Combinations

When used in fixed combination with tiotropium, consider the cautions, precautions, contraindications, and interactions associated with tiotropium.12

Asthma-related Death

Increased risk of asthma-related death reported with long-acting β2-adrenergic agonists (e.g., olodaterol).1 8 12 (See Boxed Warning.) Data from clinical trials also suggest that long-acting β2-adrenergic agonists increase the risk of asthma-related hospitalization in pediatric and adolescent patients.8 Safety and efficacy of olodaterol in patients with asthma not established; drug not indicated for treatment of asthma.1 12

Large safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed an increase in asthma-related deaths in patients receiving salmeterol.1 9 12 Increased risk of asthma-related death with salmeterol considered a class effect of long-acting β2-adrenergic agonists, including olodaterol.1 12 However, no adequate studies conducted to determine whether rate of asthma-related death is increased in patients receiving olodaterol.1 12

Not known whether death rate is increased in patients with COPD receiving long-acting β2-adrenergic agonists, including olodaterol.1 12

Other Warnings/Precautions

Deterioration of Disease and Acute Episodes

Do not initiate olodaterol in patients with acutely deteriorating COPD, which may be life-threatening.1 12

Do not use olodaterol for relief of acute symptoms.1 12 Not studied in patients with acute symptoms; do not use extra doses of the drug in such situations.1 12 Use a short-acting, inhaled β2-agonist as needed for acute symptoms.1 12

When initiating therapy, discontinue regular use (e.g., 4 times daily) of short-acting inhaled β2-agonists and use such agents only for relief of acute symptoms.1 12

Failure to respond to a previously effective dosage of olodaterol or to a supplemental short-acting, inhaled β2-agonist (e.g., increased need for additional short-acting, inhaled β2-agonists) may indicate substantially worsening COPD.1 12 Immediately reevaluate patient and treatment regimen.1 12 Do not use extra or increased dosages of olodaterol in such situations.1 12

Excessive Use and Use With Other Long-acting β2-Adrenergic Agonists

Possible fatalities and/or adverse cardiovascular effects reported in association with excessive use of inhaled sympathomimetic drugs.1 12

Do not use olodaterol more frequently or at dosages higher than recommended or concomitantly with other preparations containing long-acting β2-adrenergic agonists, since overdosage may result.1 12

Do not use olodaterol with another preparation containing a long-acting β2-agonist (e.g., arformoterol, formoterol, indacaterol, salmeterol, vilanterol) for any reason.1 12

Paradoxical Bronchospasm

Possible acute, life-threatening paradoxical bronchospasm.1 12 If paradoxical bronchospasm occurs, immediately discontinue therapy with olodaterol and institute alternative therapy.1 12

Cardiovascular Effects

Possible clinically important increases in pulse rate, systolic or diastolic BP, or symptoms of cardiovascular disease; may require discontinuance of drug.1 12

ECG changes (e.g., flattening of T wave, prolongation of corrected QT [QTc] interval, ST-segment depression) reported with β2-agonists; clinical importance unknown.1 12

Administration of larger than recommended dosages of orally inhaled olodaterol (10–50 mcg) in healthy individuals resulted in dose-related increases in QTc interval.1 12 Use with caution in patients with cardiovascular disorders (e.g., coronary insufficiency, cardiac arrhythmias, known prolongation of the QT interval, hypertrophic obstructive cardiomyopathy, hypertension).1 12

No clinically important effects on heart rate or premature beats reported in patients with COPD receiving olodaterol in clinical trials.1 12

Metabolic and Electrolyte Effects

Use with caution in patients with thyrotoxicosis.1 12

IV albuterol (IV preparation not commercially available in US) reported to aggravate preexisting diabetes mellitus and ketoacidosis.1 12 β2-Adrenergic agonists may cause hyperglycemia in some patients.1 12 Clinically important changes in serum glucose concentrations infrequent (incidence similar to placebo) in patients with COPD receiving long-term treatment with olodaterol in clinical trials.1 12

Clinically important hypokalemia (usually transient and not requiring supplementation) may occur in some patients receiving β2-adrenergic agonists; may result in adverse cardiovascular effects.1 12 (See Cardiovascular Effects under Cautions.) Hypokalemia may be potentiated by hypoxia or by concomitant treatment in patients with severe COPD; may result in increased susceptibility to arrhythmias.1 12

Clinically important changes in serum potassium concentrations infrequent (incidence similar to placebo) in patients with COPD receiving long-term treatment with olodaterol in clinical trials.1 12

Nervous System Effects

Use with caution in patients with seizure disorders and in those unusually responsive to sympathomimetic amines.1 12

Sensitivity Reactions

Immediate hypersensitivity reactions, including angioedema, reported.1 12 If a hypersensitivity reaction occurs, discontinue olodaterol immediately and consider alternative therapy.1 12

Specific Populations

Pregnancy

Category C.1 12

May interfere with uterine contractility.1 12 Carefully weigh benefit versus risk in labor.1 12

Lactation

Distributed into milk in rats.1 12 Not known whether distributed into human milk.1 12 Effects of maternal use of orally inhaled olodaterol on nursing infants not evaluated.1 12 Use caution.1 12

Pediatric Use

Not indicated for use in pediatric patients.1 12 Safety and efficacy not established.1 12

Geriatric Use

No overall differences in safety and efficacy observed between geriatric and younger adults.1 12 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics of olodaterol not substantially altered in patients with mild or moderate hepatic impairment.1 12 Not evaluated in patients with severe hepatic impairment.1 12 Dosage adjustment not required in patients with mild or moderate hepatic impairment.1 12

Renal Impairment

Olodaterol concentrations increased in patients with severe renal impairment;1 12 increases not considered clinically important.1 Not evaluated in patients with mild or moderate renal impairment.1 12 Dosage adjustment not required.1 12

Monitor patients with moderate to severe renal impairment receiving olodaterol/tiotropium in fixed combination for anticholinergic effects.12

Common Adverse Effects

Nasopharyngitis,1 2 3 12 upper respiratory tract infection,1 2 3 bronchitis,1 2 3 cough,1 2 3 12 back pain,1 2 3 12 diarrhea,1 2 3 urinary tract infection,1 2 3 dizziness,1 2 3 rash,1 arthralgia.1 3

Interactions for Olodaterol Hydrochloride

Substrate of CYP2C9 and 2C8; CYP3A4 has negligible role in metabolism.1 12 Also substrate of uridine diphosphate glucuronosyltransferase (UGT) 2B7, 1A1, 1A7, and 1A9.1 12

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (increased risk of ventricular arrhythmias and possible potentiation of olodaterol effects on the cardiovascular system).1 12

Specific Drugs

Drug

Interaction

Comments

β-Adrenergic blocking agents

Potential antagonism of pulmonary effects resulting in severe bronchospasm in patients with COPD1 12

Avoid concomitant use1 12

If concomitant therapy required, consider cautious use of cardioselective β-blocker1 12

Antidepressants, tricyclic

Potential for increased cardiovascular effects1 12

Use with extreme caution1 12

Antifungals, azole (fluconazole, ketoconazole)

Ketoconazole: Increased olodaterol exposure1 12

Fluconazole: Pharmacokinetic interaction unlikely1

No olodaterol dosage adjustment required1 12

Corticosteroids

Possible potentiation of any hypokalemic effect1 12

Diuretics, non-potassium-sparing

Potential for additive hypokalemia and/or ECG changes1 12

Clinical importance unknown; use concomitantly with caution1 12

MAO inhibitors

Potential for increased cardiovascular effects1 12

Use with extreme caution1 12

Sympathomimetic agents

Additive pharmacologic effects1 12

Avoid concomitant use of other orally inhaled, long-acting β2-agonists;1 12 use caution with concomitant adrenergic agents administered by any route1 12

Tiotropium

Pharmacokinetic interaction unlikely1 12

Xanthine derivatives

Possible potentiation of any hypokalemic effect1 12

Olodaterol Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 30%, principally due to absorption of drug delivered to the lungs.1 12

Oral bioavailability is low (<1%).1 12

Peak concentrations reached within 10–20 minutes following oral inhalation.1 7 12

Steady-state concentrations achieved after 8 days of once-daily dosing.1 12

Accumulation of olodaterol up to 1.8-fold higher following repeated dosing compared with single-dose administration.1 12

Onset

Onset of bronchodilation observed within 5 minutes following first dose.3

Duration

Bronchodilation generally persists for 24 hours.1 5 6 7 12

Special Populations

Olodaterol concentrations increased by approximately 40% in patients with severe renal impairment compared with patients with normal renal function.1 12

Distribution

Extent

Extensively distributed into tissue.1 12

Distributed into milk in rats.1 12 Not known whether distributed into human milk.1 12

Plasma Protein Binding

Approximately 60%; binding independent of drug concentration.1 12

Elimination

Metabolism

Extensively metabolized by direct glucuronidation and O-demethylation followed by conjugation.1 12

UGT 2B7, 1A1, 1A7, and 1A9 involved in direct glucuronidation of the drug; O-demethylation mediated by CYP2C9 and 2C8, with negligible contribution by CYP3A4.1 12

Unconjugated demethylated metabolite binds to β2-receptors; not detectable in plasma after repeated inhalation of recommended dosage.1 12

Elimination Route

Following oral administration, approximately 9 and 84% of a radiolabeled dose excreted in urine and feces, respectively.1 12

Following oral inhalation, approximately 5–7% of an administered dose is excreted as unchanged drug in urine.1 12

Half-life

Effective half-life of 7.5 hours in patients with COPD receiving orally inhaled olodaterol 5 mcg daily.1 12

Stability

Storage

Oral Inhalation

25°C (may be exposed to 15–30°C); do not freeze.1 12

Actions

  • Synthetic sympathomimetic amine.1 12

  • Relatively selective, long-acting β2-adrenergic agonist.1 2 3 4 5 7 11 12

  • In vitro agonist activity at β2-adrenergic receptors is 241-fold and 2299-fold the activity at β1- and β3-adrenergic receptors, respectively; clinical importance unknown.1 12

  • Increases concentrations of cyclic adenosine-3',5'-monophosphate (cAMP), resulting in relaxation of bronchial smooth muscle.1 11 12

  • May have anti-inflammatory effect in immune cells (e.g., neutrophils, mast cells) and reduce profibrotic activity in human lung fibroblasts.5 11

Advice to Patients

  • Provide copy of the manufacturer's patient information (medication guide) and instructions for use to all patients each time drug is dispensed.1 12 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time prescription is refilled.1 12

  • Importance of informing patients that long-acting β2-adrenergic agonists (including olodaterol) increase the risk of asthma-related death and that olodaterol is not indicated for the treatment of asthma.1 8 12

  • Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system (Respimat).1 12

  • Importance of not using olodaterol to relieve acute COPD symptoms; do not use extra doses for such symptoms.1 12

  • Importance of advising patients that if a dose is missed, to take the dose as soon as it is remembered; importance of not taking more than one dose (2 inhalations) in a 24-hour period.1 12

  • Importance of all patients being provided with and instructed in the use of a short-acting, inhaled β2-agonist as treatment for acute COPD symptoms.1 12

  • Importance of discontinuing regular use of short-acting, inhaled β2-agonists when initiating olodaterol and using short-acting, inhaled β2-agonists to relieve acute symptoms.1 12

  • Importance of contacting a clinician immediately if symptoms worsen, the short-acting β2-agonist becomes less effective or more inhalations than usual are required to relieve symptoms, or clinically important decrease in lung function occurs.1 12

  • Importance of advising patients receiving olodaterol not to use other long-acting, inhaled β2-agonists.1 12

  • Importance of patients not discontinuing therapy without medical supervision, since symptoms may recur after discontinuance.1 12

  • Importance of informing patients of adverse effects associated with β2-agonists (e.g., palpitations, chest pain, tachycardia, tremor, nervousness).1 12

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 12

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiac disease, hypertension, seizures, thyroid disease, diabetes mellitus, allergies to drugs or food).1 12

  • Importance of informing patients of other important precautionary information.1 12 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Olodaterol Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Solution for inhalation

2.5 mcg (of olodaterol) per metered spray

Striverdi Respimat

Boehringer Ingelheim

Olodaterol Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Solution for inhalation

2.5 mcg (of olodaterol) with Tiotropium Bromide 2.5 mcg (of tiotropium) per metered spray

Stiolto Respimat

Boehringer Ingelheim

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Boehringer Ingelheim Pharmaceuticals, Inc. Striverdi Respimat (olodaterol) inhalation spray for oral inhalation prescribing information. Ridgefield, CT; 2014 Aug.

2. Koch A, Pizzichini E, Hamilton A et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014; 9:697-714. [PubMed 25045258]

3. Ferguson GT, Feldman GJ, Hofbauer P et al. Efficacy and safety of olodaterol once daily delivered via Respimat in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014; 9:629-45. [PubMed 24966672]

4. Feldman GJ, Bernstein JA, Hamilton A et al. The 24-h FEV1 time profile of olodaterol once daily via Respimat and formoterol twice daily via Aerolizer in patients with GOLD 2-4 COPD: results from two 6-week crossover studies. Springerplus. 2014; 3:419. [PubMed 25187881]

5. Bouyssou T, Casarosa P, Naline E et al. Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010; 334:53-62. [PubMed 20371707]

6. Casarosa P, Kollak I, Kiechle T et al. Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol. J Pharmacol Exp Ther. 2011; 337:600-9. [PubMed 21357659]

7. van Noord JA, Smeets JJ, Drenth BM et al. 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011; 24:666-72. [PubMed 21839850]

8. Food and Drug Administration. FDA drug safety communication: Drug labels now contain updated recommendations on the appropriate use of long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Jun 2. Available from FDA website. Accessed 2015 Jul 1.

9. Food and Drug Administration. FDA drug safety communication: New safety requirements for long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Feb 18. Available from FDA website. Accessed 2015 Jul 1.

10. Food and Drug Administration. FDA drug safety communication: FDA requires post-market safety trials for long-acting beta-agonists (LABAs). Rockville, MD; 2011 Apr 15. Available from FDA website. Accessed 2015 Jul 1.

11. Gibb A, Yang LP. Olodaterol: first global approval. Drugs. 2013; 73:1841-6. [PubMed 24158691]

12. Boehringer Ingelheim Pharmaceuticals, Inc. Stiolto Respimat (tiotropium bromide and olodaterol) inhalation spray for oral inhalation use prescribing information. Ridgefield, CT; 2015 Jun.

13. Buhl R, Maltais F, Abrahams R et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 2015; 45:969-79. [PubMed 25573406]

14. Muruganandan S, Jayaram L. Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2015; 10:1179-89. [PubMed 26124657]

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