Stiolto Respimat - Drug Monograph

Introduction

Stiolto Respimat (tiotropium bromide/olodaterol) is a combination inhalation therapy indicated for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). This fixed-dose combination brings together two bronchodilators with complementary mechanisms of action to provide sustained improvement in lung function.

Mechanism of Action

Stiolto combines two distinct bronchodilator agents:

• Tiotropium bromide: A long-acting muscarinic antagonist (LAMA) that inhibits M3 muscarinic receptors in bronchial smooth muscle, reducing cholinergic-mediated bronchoconstriction
• Olodaterol: A long-acting beta2-adrenergic agonist (LABA) that activates beta2-adrenergic receptors, stimulating adenylate cyclase and increasing cyclic AMP levels, resulting in bronchodilation

This dual mechanism provides bronchodilation through both anticholinergic and sympathomimetic pathways, resulting in additive effects on airflow improvement.

Indications

FDA-approved for:

• Long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema
• Not indicated for the relief of acute bronchospasm or for the treatment of asthma

Dosage and Administration

• Use only with the Respimat inhaler device
• Prime before first use and if not used for >21 days
• Administer at the same time each day
• Do not exceed two inhalations daily

• Renal impairment: Use with caution in moderate to severe impairment
• Hepatic impairment: No dosage adjustment necessary
• Geriatric: No dosage adjustment required
• Pediatrics: Not recommended for patients under 18 years

Pharmacokinetics

• Tiotropium: Protein binding 72%, volume of distribution 32 L/kg
• Olodaterol: Protein binding 60%, volume of distribution 1,870 L

• Tiotropium: Minimally metabolized (CYP2D6, CYP3A4)
• Olodaterol: Extensive metabolism via glucuronidation and O-demethylation

• Tiotropium: Half-life 25-45 hours, primarily renal excretion (70%)
• Olodaterol: Half-life 7-9 hours, primarily fecal excretion (60%)

Contraindications

• Hypersensitivity to tiotropium, olodaterol, or any component of the formulation
• Patients with a history of hypersensitivity reactions to atropine or its derivatives

Warnings and Precautions

• Paradoxical bronchospasm: Discontinue immediately if occurs
• Cardiovascular effects: May cause increases in blood pressure, heart rate, and ECG changes
• Worsening of narrow-angle glaucoma: Use with caution in patients with history of glaucoma
• Worsening of urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction
• Hypokalemia and hyperglycemia: May occur, especially in susceptible patients
• Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, or cardiovascular disorders

Drug Interactions

• Beta-blockers: May antagonize bronchodilator effects
• Diuretics: May potentiate hypokalemic effects
• MAO inhibitors, tricyclic antidepressants: May potentiate cardiovascular effects
• Other anticholinergic medications: Additive anticholinergic effects
• QT-prolonging agents: Potential additive effects on cardiac repolarization
• CYP2D6 inhibitors: May increase tiotropium concentrations

Adverse Effects

• Nasopharyngitis (11%)
• Cough (6%)
• Back pain (4%)
• Urinary tract infection (4%)
• Headache (4%)
• Diarrhea (3%)
• Dizziness (2%)
• Dry mouth (2%)

• Paradoxical bronchospasm
• Cardiovascular effects (angina, hypertension, arrhythmias)
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention
• Hypersensitivity reactions (urticaria, rash, bronchospasm)

Monitoring Parameters

• Pulmonary function tests (FEV1)
• Cardiovascular status (BP, heart rate, ECG if indicated)
• Ophthalmic examination in patients with glaucoma risk factors
• Assessment of urinary symptoms in patients with BPH

• Pulmonary function (at regular intervals)
• Cardiovascular parameters (periodic assessment)
• Serum potassium and glucose in susceptible patients
• Assessment for anticholinergic side effects
• Inhaler technique at each visit
• Monitoring for disease exacerbations

Patient Education

• Use once daily at the same time each day, not for acute symptoms
• Prime inhaler before first use and if unused for >21 days
• Do not exceed prescribed dosage
• Learn proper inhaler technique: Breathe in slowly and deeply, hold breath for 10 seconds
• Rinse mouth after inhalation to reduce dry mouth and oral candidiasis risk
• Seek immediate medical attention for worsening breathing problems, chest pain, eye pain, or urinary difficulties
• Inform all healthcare providers about Stiolto use
• Keep rescue medication available at all times
• Do not stop other COPD medications unless directed by healthcare provider
• Store at room temperature, away from moisture

References

1. FDA Prescribing Information: Stiolto Respimat (2023) 2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2024 Report) 3. Ferguson GT, et al. Efficacy of tiotropium + olodaterol in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2016;39:1-8 4. Bateman ED, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42(6):1484-1494 5. Donohue JF, et al. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD: results of the 3-year ASCENT study. Pulm Pharmacol Ther. 2016;39:1-8 6. ClinicalTrials.gov: TONADO 1 and 2 studies (NCT01431274, NCT01431287) 7. American Thoracic Society/European Respiratory Society standards for the diagnosis and management of patients with COPD