Ohtuvayre

1 INDICATIONS AND USAGE OHTUVAYRE is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients. OHTUVAYRE is a phosphodiesterase 3 (PDE3) inhibitor and phosphodiesterase 4 (PDE4) inhibitor indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of OHTUVAYRE is 3 mg (one unit-dose ampule) twice daily, once in the morning and once in the evening, administered by oral inhalation using a standard jet nebulizer with a mouthpiece. Recommended Dosage : 3 mg (one ampule) twice daily administered by oral inhalation using a standard jet nebulizer with a mouthpiece. ( 2 ) See full prescribing information for administration instructions. ( 2 ) Administration Instructions Remove OHTUVAYRE unit-dose ampule from foil pouch only immediately before use. For pouches of 5 ampules, remove one ampule and place the remaining ampules back into the pouch until next use. Once the foil pouch is opened, discard ampules if not used within 14 days. Shake OHTUVAYRE ampule vigorously. Squeeze and completely empty contents of the ampule into the nebulizer cup for administration of OHTUVAYRE by oral inhalation. Discard ampule with any residual content. Administer OHTUVAYRE by oral inhalation using a standard jet nebulizer equipped with a mouthpiece, connected to an air compressor [see Instructions for Use ] . Drug Compatibility Compatibility of OHTUVAYRE mixed with other drugs has not been established. OHTUVAYRE should not be physically mixed with other drugs or added to solutions containing other drugs.

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.

4 CONTRAINDICATIONS OHTUVAYRE is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product. OHTUVAYRE is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product. ( 4 )

8.1 Pregnancy Risk Summary There are no available data on OHTUVAYRE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, administration of inhaled ensifentrine at exposures 30 times the exposure at the maximum recommended human daily inhalation dose (MRHDID) to male rats for 10 weeks prior to mating with untreated females produced increased pre- and post- implantation loss, and decreased live embryos in untreated female rats. No adverse developmental effects were observed with inhalation administration of ensifentrine to pregnant rats and rabbits during organogenesis at maternal exposures up to 79 and 9 times the exposure at MRHDID, respectively. No adverse developmental effects were observed after inhaled administration of ensifentrine to pregnant rats from the period of organogenesis through lactation at exposures up to approximately 79 times the MRHDID. (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a male fertility study, ensifentrine was administered to male rats at inhalation doses of 2, 6, and 16 mg/kg/day (4, 13, and 30 times the exposure at the MRHDID) for 10 weeks prior to mating to untreated females. Adverse effects at 16 mg/kg/day (30 times the exposure at the MRHDID) on reproductive performance included increased pre- and post- implantation loss, and decreased live embryos per litter in untreated females. No developmental toxicity was observed in rats at 6 mg/kg/day (13 times the exposure at the MRHDID). In an embryo-fetal development study, pregnant rats were administered ensifentrine at inhalation doses of up to 15 mg/kg/day (79 times the exposure at the MRHDID) during the period of organogenesis from gestation Days 6 to 17. Ensifentrine did not cause adverse effects to the fetus at exposures up to 79 times the MRHDID (on an AUC basis at a maternal inhalation dose of 15 mg/kg/day). In an embryo-fetal development study, pregnant rabbits were administered ensifentrine at inhalation doses of up to 12 mg/kg/day (9 times the exposure at the MRHDID) during the period of organogenesis from gestation Days 6 to 19. Ensifentrine did not cause adverse effects to the fetus at maternal exposures up to 9 times the MRHDID. In a pre- and post-natal development (PPND) study, pregnant rats were administered ensifentrine at inhalation doses of up to 19 mg/kg/day (approximately 79 times the exposure at the MRHDID) from gestation day 6 to lactation/post-partum day 24. No adverse effects were observed in the offspring exposed daily from birth ( in utero ) through lactation at maternal pulmonary deposited doses up to approximately 79 times the MRHDID.

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.