ENSIFENTRINE: 410 Adverse Event Reports & Safety Profile

OHTUVAYRE (ensifentrine) is a sterile, yellow to pale yellow aqueous inhalation suspension of ensifentrine for oral inhalation. Ensifentrine, the active component of OHTUVAYRE, is an inhibitor of phosphodiesterases 3 and 4 (PDE3 and PDE4). The chemical name for ensifentrine is N -(2-{(2 E )-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2 H -pyrimido[6,1- a ]isoquinolin-3(4 H )-yl}ethyl)urea; its structural formula is: Ensifentrine has a molecular weight of 477.56 and its empirical formula is C 26 H 31 N 5 O 4 . Ensifentrine is a yellow to pale yellow crystalline powder which is practically insoluble in water. OHTUVAYRE is supplied as 2.5 mL of sterile ensifentrine (1.2 mg/mL) suspension packaged in a unit-dose low-density polyethylene ampule overwrapped in a sealed foil pouch. Each unit-dose ampule contains 3 mg ensifentrine suspended in a pH 6.7 aqueous solution containing dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 20, sodium chloride, sorbitan monolaurate and water for injection. The ampule containing OHTUVAYRE should be shaken vigorously to ensure complete resuspension of the active ingredient immediately prior to administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the nebulization system used, and compressor performance. Using the PARI LC Sprint® jet nebulizer attached to a PARI Vios Pro® compressor under in vitro conditions, the mean delivered dose from the mouthpiece was approximately 933 micrograms (31% of label claim) at a mean flow rate of approximately 5 liters per minute. The mean nebulization time was approximately 7 minutes. The mass median aerodynamic diameter (MMAD) of the nebulized particles/droplets using the PARI LC Sprint® jet nebulizer attached to a PARI Vios Pro® compressor (flow rate approximately 15 L per minute, nebulization time approximately 10 minutes) is 5.82 microns (geometric standard deviation = 1.97) with a typical fine particle dose (mass of aerosolized drug < 5 microns) of approximately 614 micrograms, as determined using the Next Generation Impactor (NGI) method, based on USP <601>. OHTUVAYRE should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow and equipped with a mouthpiece.

Chemical

Structure

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 )

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.

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 )

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 Verona Pharma at 888-672-0371 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> 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.