Ohtuvayre

5 WARNINGS AND PRECAUTIONS Should not use OHTUVAYRE to treat acute symptoms of bronchospasm. ( 5.1 ) If paradoxical bronchospasm occurs, discontinue OHTUVAYRE and institute alternative therapy. ( 5.2 ) An increase in psychiatric adverse reactions, including suicidality, were reported with use of OHTUVAYRE. Carefully weigh the risks and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. ( 5.3 ) 5.1 Acute Episodes of Bronchospasm OHTUVAYRE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. OHTUVAYRE has not been studied in the relief of acute symptoms and extra doses of OHTUVAYRE should not be used for that purpose. The safety and effectiveness of OHTUVAYRE for relief of acute symptoms have not been established. Acute symptoms should be treated with an inhaled, short-acting bronchodilator. 5.2 Paradoxical Bronchospasm As with other inhaled medicines, OHTUVAYRE may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with OHTUVAYRE, it should be treated immediately with an inhaled, short-acting bronchodilator. OHTUVAYRE should be discontinued immediately and alternative therapy should be instituted. 5.3 Psychiatric Events Including Suicidality Treatment with OHTUVAYRE is associated with an increase in psychiatric adverse reactions. Psychiatric events including suicide-related adverse reactions were reported in clinical studies in patients who received OHTUVAYRE. One patient who received OHTUVAYRE in the pooled 24-week safety population [see Adverse Reactions (6.1) ] experienced a suicide-related adverse reaction (suicide attempt), and in another controlled study, one patient who received ensifentrine experienced a suicide-related adverse reaction (suicide). Additionally, the most commonly reported psychiatric adverse reactions in the pooled 24-week safety population were insomnia (6 patients [0.6%] OHTUVAYRE 3 mg; 2 patients [0.3%] placebo), and anxiety (2 patients [0.2%] OHTUVAYRE 3 mg; 1 patient [0.2%] placebo). Depression-related reactions including depression, major depression, and adjustment disorder with depressed mood occurred in 4 patients [0.4%] receiving OHTUVAYRE and no patients receiving placebo. Before initiating treatment with OHTUVAYRE, healthcare providers should carefully weigh the risk and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. Healthcare providers should carefully evaluate the risks and benefits of continuing treatment with OHTUVAYRE if such events occur.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Paradoxical Bronchospasm [see Warnings and Precautions (5.2) ] Psychiatric Events Including Suicidality [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence greater and equal to 1% and more common than placebo) include back pain, hypertension, urinary tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-800-672-6372 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OHTUVAYRE was based on the pooled safety population from two randomized, double-blind, placebo-controlled trials (ENHANCE-1 and ENHANCE-2) for 24 weeks, and a 48-week cohort that assessed safety in ENHANCE-1. In these trials, a total of 975 patients received 3 mg of OHTUVAYRE twice daily administered by oral inhalation using a standard jet nebulizer [see Clinical Studies (14) ] . The safety population included all patients who were randomized and received at least one dose of OHTUVAYRE or placebo. Adverse reactions that occurred at an incidence greater than or equal to 1% in OHTUVAYRE and were more common than placebo in the pooled population are provided in Table 1. The proportion of patients who discontinued treatment due to adverse reactions was 7.6% for the OHTUVAYRE-treated patients and 8.2% for placebo-treated patients. Table 1. Adverse Reactions with OHTUVAYRE with incidence ≥ 1% and More Common than Placebo in Patients with COPD in the Pooled 24-Week Safety Population (ENHANCE-1 and ENHANCE-2) Adverse Reaction OHTUVAYRE N=975 n (%) Placebo N=574 n (%) Back pain 18 (1.8%) 6 (1.0%) Hypertension 17 (1.7%) 5 (0.9%) Urinary tract infection 13 (1.3%) 6 (1.0%) Diarrhea 10 (1.0%) 4 (0.7%) Adverse Reactions in the 48-Week Cohort In the 48-week cohort of ENHANCE-1, 369 patients were enrolled to be treated with 3 mg OHTUVAYRE (N=280) or placebo (N=89) twice daily for 48 weeks [see Clinical Studies (14) ] . The adverse reactions reported in the 48-week cohort were consistent with those observed in the pooled 24-week safety population.

<table width="80%"><caption>Table 1. Adverse Reactions with OHTUVAYRE with incidence &#x2265; 1% and More Common than Placebo in Patients with COPD in the Pooled 24-Week Safety Population (ENHANCE-1 and ENHANCE-2)</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reaction</th><th styleCode="Rrule" valign="top">OHTUVAYRE N=975 n (%)</th><th styleCode="Rrule" valign="top">Placebo N=574 n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">18 (1.8%)</td><td styleCode="Rrule">6 (1.0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">17 (1.7%)</td><td styleCode="Rrule">5 (0.9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">13 (1.3%) </td><td styleCode="Rrule">6 (1.0%)</td></tr><tr><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">10 (1.0%)</td><td styleCode="Rrule">4 (0.7%)</td></tr></tbody></table>