Brinsupri

5 WARNINGS AND PRECAUTIONS Dermatologic Adverse Reactions : Monitor for new rash or skin conditions and refer to dermatology for evaluation. ( 5.1 ) Gingival and Periodontal Adverse Reactions : Gingival and periodontal adverse reactions can occur with BRINSUPRI use. Refer to the dental care services for regular dental checkups and advise patients to perform routine dental hygiene. ( 5.2 ) Live Attenuated Vaccines : It is unknown whether administration of live attenuated vaccines during BRINSUPRI treatment will affect the safety or effectiveness of the vaccines. Avoid use of live attenuated vaccines. ( 5.3 ) 5.1 Dermatologic Adverse Reactions Treatment with BRINSUPRI is associated with an increase in dermatologic adverse reactions, including rash, dry skin, and hyperkeratosis [see Adverse Reactions (6.1) ]. Monitor patients for development of new rashes or skin conditions and refer patients to a dermatologist for evaluation of new dermatologic findings. 5.2 Gingival and Periodontal Adverse Reactions Treatment with BRINSUPRI is associated with an increase in gingival and periodontal adverse reactions [see Adverse Reactions (6.1) ]. Refer patients to dental care services for regular dental checkups while taking BRINSUPRI. Advise patients to perform routine dental hygiene. 5.3 Live Attenuated Vaccines The concomitant use of BRINSUPRI and live attenuated vaccines has not been evaluated. It is unknown whether administration of live attenuated vaccines during BRINSUPRI treatment will affect the safety or effectiveness of these vaccines. The use of live attenuated vaccines should be avoided in patients receiving BRINSUPRI.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Dermatologic Adverse Reactions [see Warnings and Precautions (5.1) ] Gingival and Periodontal Adverse Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥2%): upper respiratory tract infection, headache, rash, dry skin, hyperkeratosis, hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Insmed Incorporated at 1-844-4-INSMED or FDA at 1-800-FDA-1088 or https://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 data below reflect the safety of BRINSUPRI in adult and pediatric patients aged 12 years and older with non-cystic fibrosis bronchiectasis (NCFB). A total of 1721 patients with NCFB were randomized in a double-blind, placebo-controlled clinical trial of 52 weeks duration (ASPEN) [see Clinical Studies (14) ]. The safety of BRINSUPRI was based on data from 1719 adult and pediatric patients aged 12 years and older who received at least one dose of BRINSUPRI or placebo. A total of 1156 patients received at least one dose of BRINSUPRI 10 mg or 25 mg orally once daily. Table 1 shows the adverse reactions occurring at an incidence of ≥2% and higher in BRINSUPRI-treated patients compared to placebo in the safety population from ASPEN. Table 1 Adverse Reactions with BRINSUPRI with an Incidence of ≥2% and More Common than Placebo in ASPEN Adverse Reaction Placebo (N=563) n (%) BRINSUPRI 10 mg QD (N=582) n (%) BRINSUPRI 25 mg QD (N=574) n (%) Upper respiratory tract infection Upper respiratory tract infection includes coronavirus infection, COVID-19, influenza, upper respiratory tract infection, viral infection, and viral upper respiratory tract infection. 141 (25) 157 (27) 169 (29) Headache 39 (7) 39 (7) 49 (9) Rash Rash includes rash, rash maculo-papular, rash pruritic, rash erythematous, dermatitis, and erythema. 22 (4) 25 (4) 35 (6) Dry skin Dry skin includes dry skin, chapped lips, cheilitis, lip dry, skin exfoliation, skin fissures, xeroderma, and xerosis. 8 (1) 17 (3) 25 (4) Hyperkeratosis Hyperkeratosis includes hyperkeratosis, palmoplantar keratoderma, and skin hypertrophy. 5 (1) 8 (1) 16 (3) Hypertension 17 (3) 28 (5) 13 (2) Adverse Reactions in WILLOW A total of 256 adult patients with NCFB were randomized in the 24-week, double-blind, placebo-controlled clinical trial (WILLOW). Of those randomized, 255 adult patients received BRINSUPRI 10 mg, BRINSUPRI 25 mg, or placebo, which consisted of 170 adults treated with at least one dose of BRINSUPRI 10 mg or 25 mg orally once daily. The safety profile for adult patients with NCFB in WILLOW was generally similar to ASPEN, with the exception of a higher incidence of gingival and periodontal adverse reactions. The incidence of gingival and periodontal adverse reactions in WILLOW among patients treated with BRINSUPRI 10 mg and 25 mg were 9.9% and 10.1%, respectively, compared to 2.4% in placebo-treated patients. Less Common Adverse Reactions Liver Function Test Elevations In ASPEN, there was an increase from baseline in average ALT, AST, and alkaline phosphatase levels at all time points from Week 4 through Week 56 in both BRINSUPRI 10 mg and 25 mg arms compared to placebo. The incidence of ALT >3× upper limit of normal (ULN) was 0%, 1.2%, and 0.9%, in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively. The incidence of AST >3× ULN was 0.2%, 0.3%, and 0.5% in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively. The incidence of alkaline phosphatase >1.5× ULN was 2.5%, 4.1%, and 4.0% in patients treated with placebo and BRINSUPRI 10 mg and 25 mg, respectively. Skin Cancers In ASPEN, the incidence of skin cancers among patients treated with BRINSUPRI 10 mg and 25 mg was 0.5% and 1.9%, respectively, compared to 1.1% in placebo-treated patients. Alopecia In ASPEN, the incidence of alopecia among patients treated with BRINSUPRI 10 mg and 25 mg was 1.5% and 1.6%, respectively, compared to 0.4% in placebo-treated patients.

<table width="85%" ID="Table1"><caption>Table 1 Adverse Reactions with BRINSUPRI with an Incidence of &#x2265;2% and More Common than Placebo in ASPEN</caption><col width="30%" align="left" valign="top"/><col width="23%" align="center" valign="top"/><col width="23%" align="center" valign="top"/><col width="24%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">Placebo (N=563) n (%)</th><th styleCode="Rrule">BRINSUPRI 10 mg QD (N=582) n (%)</th><th styleCode="Rrule">BRINSUPRI 25 mg QD (N=574) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection<footnote>Upper respiratory tract infection includes coronavirus infection, COVID-19, influenza, upper respiratory tract infection, viral infection, and viral upper respiratory tract infection.</footnote></td><td styleCode="Rrule">141 (25)</td><td styleCode="Rrule">157 (27)</td><td styleCode="Rrule">169 (29)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">39 (7)</td><td styleCode="Rrule">39 (7)</td><td styleCode="Rrule">49 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<footnote>Rash includes rash, rash maculo-papular, rash pruritic, rash erythematous, dermatitis, and erythema.</footnote></td><td styleCode="Rrule">22 (4)</td><td styleCode="Rrule">25 (4)</td><td styleCode="Rrule">35 (6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry skin<footnote>Dry skin includes dry skin, chapped lips, cheilitis, lip dry, skin exfoliation, skin fissures, xeroderma, and xerosis.</footnote></td><td styleCode="Rrule">8 (1)</td><td styleCode="Rrule">17 (3)</td><td styleCode="Rrule">25 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperkeratosis<footnote>Hyperkeratosis includes hyperkeratosis, palmoplantar keratoderma, and skin hypertrophy.</footnote></td><td styleCode="Rrule">5 (1)</td><td styleCode="Rrule">8 (1)</td><td styleCode="Rrule">16 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">17 (3)</td><td styleCode="Rrule">28 (5)</td><td styleCode="Rrule">13 (2)</td></tr></tbody></table>