Stiolto Respimat
tiotropium bromide / olodaterol
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| COPD — long-term maintenance treatment | Adults | Dual bronchodilator (LAMA + LABA) | FDA Approved |
Tiotropium-olodaterol is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. The tiotropium component also has a demonstrated benefit in reducing COPD exacerbations. It delivers the combination as a slow-moving aerosol mist via the Respimat soft mist inhaler, which is device-independent of inspiratory effort and may be preferable for patients with poor inspiratory flow rates.
Stiolto Respimat is NOT indicated for asthma. The PI carries a boxed warning regarding the risk of asthma-related death with LABA monotherapy (without ICS). Use of olodaterol without an ICS in patients with asthma is contraindicated. For asthma patients needing a LAMA, tiotropium monotherapy (Spiriva Respimat) is approved for add-on to ICS therapy.
None well-established. Unlike tiotropium monotherapy (which is FDA-approved for asthma), the fixed-dose tiotropium-olodaterol combination has no established off-label uses due to the LABA asthma contraindication. Evidence quality: N/A.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| COPD maintenance — initial dual bronchodilator therapy | 2 inhalations (5/5 mcg) once daily | 2 inhalations once daily | 2 inhalations/24 h | Single dose strength; do not exceed 2 puffs per day Use at the same time each day |
| COPD — step-up from LAMA or LABA monotherapy | 2 inhalations (5/5 mcg) once daily | 2 inhalations once daily | 2 inhalations/24 h | Discontinue separate LAMA and/or LABA inhalers when switching Tiotropium component also reduces exacerbation risk per DYNAGITO trial |
| COPD — patients with poor inspiratory flow | 2 inhalations (5/5 mcg) once daily | 2 inhalations once daily | 2 inhalations/24 h | Respimat SMI delivers consistent dose independent of inspiratory effort Preferred for patients who cannot generate adequate flow for DPI devices |
Unlike dry powder inhalers, the Respimat SMI generates a slow-moving aerosol mist using mechanical energy, independent of the patient’s inspiratory effort. Key points: (1) Insert cartridge and prime with 4 sprays toward the ground before first use. (2) If unused for more than 3 days, fire 1 spray toward ground to re-prime; if unused for more than 21 days, re-prime with 4 sprays. (3) Two puffs = one dose; breathe in slowly and deeply while pressing the dose-release button. (4) Hold breath for 10 seconds or as long as comfortable. (5) Do not spray into the eyes. (6) Discard 3 months after first use, even if medication remains. The dose counter shows how many doses are left.
Pharmacology
Mechanism of Action
Tiotropium is a long-acting muscarinic antagonist with similar binding affinity for the M1 through M5 receptor subtypes. Its therapeutic effect in COPD is primarily through sustained, competitive blockade of M3 receptors on bronchial smooth muscle. Tiotropium dissociates very slowly from M3 receptors (receptor dissociation half-life approximately 35 hours), which accounts for its prolonged duration of action exceeding 24 hours and supports once-daily administration. It also reduces mucus secretion via M3 blockade on submucosal glands.
Olodaterol is a selective, long-acting beta-2 adrenergic agonist (LABA) with a receptor dissociation half-life of approximately 17.8 hours. By activating beta-2 receptors on airway smooth muscle, it stimulates adenylyl cyclase and increases intracellular cyclic AMP, producing sustained bronchial smooth muscle relaxation. Olodaterol has nearly full intrinsic activity at the beta-2 receptor (88% relative to isoprenaline). The combination of cholinergic and adrenergic bronchodilation provides additive effects greater than either monotherapy alone.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | TIO: Tmax 5–7 min; bioavailability ~33% (Respimat); oral bioavailability 2–3%. OLO: rapid pulmonary absorption; bioavailability ~30% (inhaled) | Both components reach peak levels within minutes; systemic exposure primarily from lung-absorbed fraction; food does not affect absorption |
| Distribution | TIO: Vd 32 L/kg (IV); protein binding 72%. OLO: Vd ~1,110 L; protein binding ~60% | Tiotropium distributes widely into tissues with preferential lung retention; olodaterol has very high tissue distribution |
| Metabolism | TIO: minimal metabolism; non-enzymatic ester cleavage to inactive products + minor CYP2D6/3A4 oxidation. OLO: UGT2B7 (direct glucuronidation), CYP2C9/2C8 (O-demethylation); P-gp substrate | Tiotropium is largely excreted unchanged; ketoconazole increases olodaterol Cmax/AUC by ~1.7-fold but no dose adjustment needed |
| Elimination | TIO: t½ ~25 h (inhaled COPD); renal 74% (IV, unchanged); total clearance 880 mL/min. OLO: fecal 53%, urinary 38% (IV); unchanged olodaterol 19% in urine (IV) | Both support once-daily dosing; tiotropium clearance is predominantly renal (monitor in severe renal impairment: AUC increased 94%); PK steady state at day 7 for both |
Side Effects
| Adverse Effect | Incidence (Stiolto / TIO / OLO) | Clinical Note |
|---|---|---|
| Nasopharyngitis | 12.4% / 11.7% / 12.6% | Most frequently reported event; similar across all treatment arms; generally mild upper respiratory symptoms |
| Adverse Effect | Incidence (Stiolto / TIO / OLO) | Clinical Note |
|---|---|---|
| Cough | 3.9% / 4.4% / 3.0% | Higher than olodaterol arm; may relate to the Respimat mist or tiotropium anticholinergic drying effect |
| Back pain | 3.6% / 1.8% / 3.4% | Higher than tiotropium monotherapy; musculoskeletal complaint not clearly dose-related |
Additional adverse events occurring in ≤3% of patients included: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, GERD, epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis, atrial fibrillation, palpitations, SVT, tachycardia, hypertension, rash, pruritus, angioedema, urticaria, arthralgia, joint swelling, urinary retention, dysuria, and UTI (FDA PI).
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Paradoxical bronchospasm | Rare | Immediately after inhalation | Treat with rescue SABA; permanently discontinue Stiolto; switch to alternative |
| Anaphylaxis / angioedema | Very rare (postmarketing with tiotropium component) | Minutes to hours | Emergency treatment; permanent discontinuation; includes cross-sensitivity with ipratropium |
| Acute narrow-angle glaucoma | Rare; LAMA class effect | Hours to days | Emergency ophthalmology referral; avoid spraying into eyes; discontinue if confirmed |
| Urinary retention | Uncommon; LAMA class effect | Days to weeks | Discontinue if significant; urology referral; higher risk with BPH |
| Cardiac arrhythmias (AF, SVT, tachycardia) | ≤3% in clinical trials | Variable | ECG monitoring; discontinue if clinically significant; cardiology referral |
| Intestinal obstruction including paralytic ileus | Very rare; anticholinergic class effect | Days to weeks | Surgical consultation; discontinue anticholinergic; supportive care |
Drug Interactions
Olodaterol is metabolised by CYP2C9/2C8 and UGT enzymes and is a P-gp substrate; strong CYP and P-gp inhibitors (e.g., ketoconazole) increase olodaterol exposure by approximately 1.7-fold, but no dose adjustment is required. Tiotropium is minimally metabolised and has limited pharmacokinetic interactions. Pharmacodynamic interactions are the primary concern for both components.
Monitoring
- Lung Function (FEV1)Baseline, then every 3–6 months
RoutineAssess bronchodilator response. Trough FEV1 improvement should be evident within days. Declining FEV1 or increased rescue use signals need for therapy re-evaluation. - COPD ExacerbationsEach visit
RoutineTrack exacerbation frequency. If exacerbations persist, assess blood eosinophils and consider adding ICS (stepping up to triple therapy). - Ophthalmological SymptomsEach visit in at-risk patients
Trigger-basedLAMA class risk for narrow-angle glaucoma; Respimat mist can reach the eyes if sprayed incorrectly. Warn patients to avoid spraying into the eyes. - Urinary SymptomsEach visit in at-risk patients
Trigger-basedLAMA class effect: monitor for urinary retention in patients with BPH or bladder-neck obstruction. - Renal FunctionBaseline in elderly or those with known impairment
Trigger-basedTiotropium is predominantly renally cleared. Severe renal impairment (CrCl <30 mL/min) increases tiotropium AUC by 94% and Cmax by 52%. Monitor for anticholinergic adverse effects. - Serum PotassiumWhen concurrent diuretics or xanthines
Trigger-basedBeta-agonists cause transient hypokalaemia. In 52-week trials, no clinically significant treatment effect on potassium at standard doses.
Contraindications & Cautions
Absolute Contraindications
- Asthma: Use of LABA (olodaterol) without an ICS in asthma is contraindicated due to increased risk of asthma-related death. Stiolto Respimat is not indicated for asthma.
- Hypersensitivity to tiotropium, ipratropium (cross-sensitivity), olodaterol, or any component of the product (including benzalkonium chloride, edetate disodium).
Relative Contraindications (Specialist Input Recommended)
- Narrow-angle glaucoma: Tiotropium may precipitate or worsen acute angle-closure glaucoma. The Respimat mist can reach the eyes if misdirected.
- Prostatic hyperplasia or bladder-neck obstruction: Anticholinergic effects may worsen urinary retention.
- Severe cardiovascular disease: Olodaterol’s beta-adrenergic effects may worsen coronary insufficiency, arrhythmias, or hypertension.
- Severe renal impairment (CrCl <30 mL/min): Tiotropium AUC increased 94%; monitor closely for anticholinergic adverse effects.
Use with Caution
- Convulsive disorders, thyrotoxicosis, diabetes mellitus: Beta-agonist class precautions apply.
- Severe hepatic impairment: Olodaterol not studied in severe impairment; use with caution.
Long-acting beta-2 adrenergic agonists (LABA) such as olodaterol increase the risk of asthma-related death. The SMART trial showed a relative risk of 4.37 (95% CI: 1.25–15.34) for salmeterol monotherapy vs placebo. This is a class effect of all LABAs. Stiolto Respimat does not contain an ICS and is explicitly contraindicated for asthma use. Available data do not suggest increased death risk with LABA use in COPD. The Stiolto Respimat PI retains a formal boxed warning for this class effect.
Patient Counselling
Purpose of Therapy
Stiolto Respimat is a once-daily maintenance inhaler for COPD that combines two bronchodilators to keep airways open and reduce flare-ups. It is not a rescue inhaler. Patients must always carry a separate short-acting rescue inhaler. Stiolto is for COPD only and must never be used for asthma.
How to Take
Use Stiolto Respimat once daily at the same time each day. Take 2 puffs per dose: press the dose-release button while breathing in slowly and deeply through the mouth for each puff. Hold your breath for about 10 seconds after each puff. Do not spray into the eyes. Discard the inhaler 3 months after first use even if medicine remains. Prime the inhaler before first use by spraying 4 times toward the ground.
Sources
- Stiolto Respimat (tiotropium bromide and olodaterol) Prescribing Information. Boehringer Ingelheim. Revised July 2025. DailyMedPrimary source for all dosing, contraindications, adverse reaction data, and pharmacokinetic parameters in this monograph.
- Stiolto Respimat FDA Label (2025 revision). FDA AccessDataLatest FDA label revision incorporating exacerbation reduction data from the DYNAGITO trial.
- 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(4):969-979. doi:10.1183/09031936.00136014Pivotal 52-week Trial 1 and Trial 2 (TONADO) establishing superiority of TIO/OLO over each monotherapy in trough FEV1; primary safety database for adverse reaction rates.
- Calverley PMA, Anzueto AR, Carter K, et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO). Eur Respir J. 2018;52(4):1801014. doi:10.1183/13993003.01014-201852-week exacerbation trial (N=7,880) comparing Stiolto vs Spiriva; contributed to the updated FDA labelling for exacerbation reduction.
- Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med. 2015;109(10):1312-1319. doi:10.1016/j.rmed.2015.08.002Quality-of-life analysis from the TONADO trials confirming SGRQ improvements above the minimum clinically important difference.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD, 2024 Report. goldcopd.orgPositions LAMA/LABA dual bronchodilator therapy as recommended for symptomatic COPD patients (Group B/E) based on symptoms and exacerbation history.
- 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(1):53-62. doi:10.1124/jpet.110.167007Preclinical characterisation of olodaterol’s 24-hour bronchodilatory effect and nearly full beta-2 intrinsic activity (88%), supporting once-daily dosing.
- Disse B, Speck GA, Rominger KL, et al. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64(6–7):457-464. doi:10.1016/S0024-3205(98)00588-8Foundational characterisation of tiotropium’s slow M3 receptor dissociation kinetics (>35 h) explaining its prolonged bronchodilation.
- Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257-267. doi:10.1016/j.pupt.2010.03.003Reviews the mechanistic rationale for LAMA/LABA combination, explaining additive bronchodilation through cholinergic and adrenergic pathways.
- van Noord JA, Smeets JJ, Drenth BM, et al. 24-hour bronchodilation following a single dose of the novel beta2-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011;24(6):666-672. doi:10.1016/j.pupt.2011.07.006Demonstrates 24-hour bronchodilation from a single inhaled dose of olodaterol in COPD patients.
- Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and powder in chronic obstructive pulmonary disease. Int J Clin Pharmacol Ther. 2014;52(12):1083-1090. doi:10.5414/CP202122Characterises tiotropium PK via Respimat, including the higher systemic bioavailability (~33%) compared with dry powder (~19.5%) and implications for dose equivalence.