General Information

Stiolto Respimat is a once-daily, fixed-dose combination of tiotropium, a long-acting muscarinic antagonist and olodaterol, a long-acting beta-agonist.

Stiolto Respimat is specifically indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease.

Mechanism of Action

Stiolto Respimat is a once-daily, fixed-dose combination of tiotropium and olodaterol. Tiotropium is a long-acting, muscarinic antagonist which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. Olodaterol is a long-acting beta2-adrenergic agonist (LABA). The compound exerts its pharmacological effects by binding and activation of beta2-adrenoceptors after topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3’, 5’ adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells.

Side Effects

Adverse reactions associated with the use of Stiolto Respimat may include, but are not limited to, the following:

• nasopharyngitis
• cough
• back pain

Dosing/Administration

Stiolto Respimat is supplied as a spray for oral inhalation. The recommended dose is two inhalations once daily at the same time of the day. Do not use more than two inhalations every 24 hours. 

Clinical Trial Results

The FDA approval of Stiolto Respimat was based primarily on two four-week dose-ranging trials and two confirmatory active-controlled 52-week trials (trials 1 and 2).

Dose-Ranging Trials:

Dose selection for Stiolto Respimat was primarily based on trials for the individual components, tiotropium bromide and olodaterol. Dose selection was also supported by two randomized, double-blind, active-controlled, four-week trials. In one trial in 232 patients with COPD, three tiotropium doses (1.25, 2.5 and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy. Results demonstrated improvement in trough FEV1 for the combination when compared to olodaterol alone. The difference in trough FEV1 for the tiotropium bromide/olodaterol doses of 1.25/5, 2.5/5 and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95 percent CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively. In the second trial in 360 patients with COPD, three olodaterol doses (2, 5 and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to tiotropium monotherapy. The difference in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5 and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L (95 percent CI -0.029, 0.076), 0.033 L (-0.019, 0.085) and 0.057 L (0.004, 0.110), respectively. Results of these trials supported the evaluation of once-daily doses of tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.

Confirmatory Trials:

A total of 5,162 COPD patients (1029 receiving Stiolto Respimat, 1,038 receiving olodaterol 5 mcg and 1,033 receiving tiotropium bromide 5 mcg) were studied in two confirmatory trials of Stiolto Respimat. Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials that compared Stiolto Respimat to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products were administered via the RESPIMAT inhaler. The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years and moderate to very severe pulmonary impairment. All treatments were administered once daily in the morning. The primary endpoints were change from baseline in FEV1 AUC0-3hr and trough FEV1 after 24 weeks of treatment. In both trials 1 and 2, Stiolto Respimat demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg. The increased bronchodilator effects of Stiolto Respimat compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period. Stiolto Respimat displayed a mean increase in FEV1 from baseline of 0.137 L (range: 0.133-0.140 L) within five minutes after the first dose. Patients treated with Stiolto Respimat used less rescue medication compared to those treated with tiotropium 5 mcg and olodaterol 5 mcg.