JASCAYD

1 INDICATIONS AND USAGE JASCAYD is a phosphodiesterase 4 (PDE4) inhibitor indicated for: The treatment of idiopathic pulmonary fibrosis in adult patients. ( 1.1 ) The treatment of progressive pulmonary fibrosis in adult patients. ( 1.2 ) 1.1 Idiopathic Pulmonary Fibrosis JASCAYD is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) in adult patients. 1.2 Progressive Pulmonary Fibrosis JASCAYD is indicated for the treatment of progressive pulmonary fibrosis (PPF) in adult patients.

2 DOSAGE AND ADMINISTRATION Recommended Dosage : 18 mg orally twice daily approximately 12 hours apart with or without food. ( 2.1 ) Reduce JASCAYD to 9 mg twice daily for patients who are unable to tolerate 18 mg twice daily, except in patients taking concomitant pirfenidone. ( 2.1 , 7.1 ) Swallow tablets whole or dispersed in water. ( 2.1 ) See full prescribing information for dosage modification for concomitant use with CYP3A inhibitors and administration instructions for patients who have difficulty swallowing tablets. ( 2.2 , 2.3 ) 2.1 Recommended Dosage The recommended dosage of JASCAYD is 18 mg twice daily, administered orally (swallow tablets whole or dispersed in water) approximately 12 hours apart, with or without food. Reduce JASCAYD to 9 mg twice daily for patients who are unable to tolerate 18 mg twice daily, except in patients who concomitantly use JASCAYD with pirfenidone. Recommended Dosage for Concomitant Use with Pirfenidone Recommended dosage of JASCAYD is 18 mg twice daily when used concomitantly with pirfenidone. Do not reduce dosage to 9 mg twice daily [see Drug Interactions (7.1) ]. Administration Instructions Swallow JASCAYD tablets whole or dispersed in water [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. Missed Dose(s) If a dose of JASCAYD is missed, advise the patient to take the next dose at the next scheduled time. Advise the patient to not make up for a missed dose. Maximum Recommended Dosage The maximum recommended dosage of JASCAYD is 18 mg twice daily. 2.2 Dosage Modification of JASCAYD for Concomitant Use With CYP3A Inhibitors Strong CYP3A Inhibitors Reduce JASCAYD dosage to 9 mg twice daily when used concomitantly with strong CYP3A inhibitors [see Drug Interactions (7.1) ]. Moderate and Weak CYP3A Inhibitors No dosage modification is recommended for JASCAYD when used concomitantly with moderate or weak CYP3A inhibitors. 2.3 Administration Instructions for Patients Who Have Difficulty Swallowing Tablets Disperse JASCAYD tablet in water and administer as follows: Place approximately 100 mL (3 to 4 ounces) of non-carbonated, room temperature water in a glass. Do not use any other liquids. Place a JASCAYD tablet in the water, without crushing, and stir regularly for approximately 15 to 20 minutes until the tablet is dispersed into very small pieces (the tablet will not completely dissolve). Drink the dispersion within 2 hours of mixing. If the dispersion is not drunk immediately, stir again before drinking. Rinse the glass with approximately 100 mL (3 to 4 ounces) of water and drink to ensure the full dose is administered.

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A Inhibitors : Reduce JASCAYD dosage to 9 mg twice daily. ( 2.2 , 7.1 ) Moderate or Strong CYP3A Inducers : Avoid concomitant use with JASCAYD. ( 7.1 ) 7.1 Effects of Other Drugs on JASCAYD Strong CYP3A Inhibitors Reduce the dosage of JASCAYD to 9 mg twice daily when used concomitantly with strong CYP3A inhibitors [see Dosage and Administration (2.2) ] . Nerandomilast is a CYP3A substrate. Concomitant use of JASCAYD with a strong CYP3A inhibitor increases exposure of nerandomilast, which may increase the risk of JASCAYD adverse reactions [see Clinical Pharmacology (12.3) ]. Moderate or Strong CYP3A Inducers Avoid use of JASCAYD with strong or moderate CYP3A inducers. Nerandomilast is a CYP3A substrate. Concomitant use of JASCAYD with moderate or strong CYP3A inducers is expected to decrease exposure of nerandomilast, which may decrease the efficacy of JASCAYD [see Clinical Pharmacology (12.3) ] . Pirfenidone Recommended dosage of JASCAYD is 18 mg twice daily when used concomitantly with pirfenidone. Do not reduce the dosage to 9 mg twice daily [see Dosage and Administration (2.1) ] . Concomitant use of JASCAYD with pirfenidone decreases exposure of nerandomilast [see Clinical Pharmacology (12.3) ] . When JASCAYD was used concomitantly with pirfenidone in patients with IPF in FIBRONEER-IPF, efficacy was not observed with the JASCAYD 9 mg twice daily dosage [see Clinical Studies (14.1) ] .

8.1 Pregnancy Risk Summary There are no available data on JASCAYD use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are maternal and fetal risks associated with untreated idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) during pregnancy (Clinical Considerations). Based on findings from animal reproduction studies, JASCAYD may increase the risk for fetal loss. In an embryo-fetal development study in rats, oral administration of nerandomilast to pregnant rats during organogenesis at an exposure approximately 5 times the maximum recommended human dose (MRHD) of 36 mg/day resulted in an increase in embryo-fetal losses (see Data ) . Advise pregnant women and females of reproductive potential of the potential risk of fetal loss. 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 is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Untreated IPF or PPF can lead to respiratory failure and mortality in the mother and intrauterine growth restriction, preterm birth, fetal hypoxia, and neonatal death. Data Animal Data In an embryo-fetal development study in pregnant rats dosed by the oral route during the period of organogenesis from gestation days 6 to 17, nerandomilast caused an increase in embryo-fetal losses (pre- and post-implantation loss and decreased mean number of live fetuses) at an exposure that was approximately 5 times the MRHD (on an AUC basis with a maternal oral dose of 6 mg/kg/day). Maternal toxicity, as evidenced by decreased body weight gains and adverse clinical signs, was observed at exposures approximately 7 times the MRHD (on an AUC basis with a maternal oral dose of 9 mg/kg/day). No fetal or maternal toxicities were observed at exposures up to 3 and 5 times the MRHD (on an AUC basis with maternal oral doses of 3 mg/kg/day and 6 mg/kg/day), respectively. In an embryo-fetal development study in pregnant rabbits dosed by the oral route during the period of organogenesis from gestation days 7 to 19, no effects on maternal or fetal development were observed at an exposure that was approximately 4 times the MRHD (on an AUC basis with a maternal oral dose of 15 mg/kg/day). In a prenatal and postnatal development study in pregnant rats dosed by the oral route during the periods of gestation and lactation from gestation day 6 to lactation day 20, nerandomilast had no effects on delivery or the growth and development of offspring at an exposure that was approximately 2 times the MRHD (on an AUC basis with a maternal oral dose of 3 mg/kg/day).

6 ADVERSE REACTIONS Most common adverse reactions (≥5%) are diarrhea, COVID-19, upper respiratory tract infection, depression, weight decreased, decreased appetite, nausea, fatigue, headache, vomiting, back pain, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 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 clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions for Idiopathic Pulmonary Fibrosis The safety of JASCAYD was based on a randomized, placebo-controlled, double-blind trial (FIBRONEER-IPF), which included 1,177 adult patients with IPF who were randomized in a 1:1:1 ratio to receive JASCAYD 9 mg twice daily, JASCAYD 18 mg twice daily, or matching placebo. Patients received JASCAYD or placebo with or without background antifibrotic treatment (nintedanib or pirfenidone) for at least 52 weeks [see Clinical Studies (14.1) ] . The median duration of exposure was 14 months in each treatment arm. Discontinuation due to adverse reactions occurred more frequently in patients treated with JASCAYD (with or without background antifibrotic treatment) 18 mg (15%) and 9 mg (12%) compared to placebo (11%). The most frequent adverse reaction leading to discontinuation of JASCAYD 18 mg and 9 mg was diarrhea (6% and 2%, respectively). Table 1 lists the most common adverse reactions from the studied population with an incidence of greater than or equal to 5% in JASCAYD-treated patients and more common than the placebo group. Table 1 Adverse Reactions with JASCAYD with Incidence of ≥5% and More Common than Placebo in Patients 1 with IPF (FIBRONEER-IPF Trial) JASCAYD 18 mg BID n=392 JASCAYD 9 mg BID n=392 Placebo n=393 1 Studied population including patients who received JASCAYD with or without background antifibrotic treatment (nintedanib or pirfenidone) 2 Includes depression, depressed mood, depression rating scale score increased, suicidal ideation, adjustment disorder with depressed mood, depressive symptom BID: twice daily; COVID-19: infection with SARS-CoV-2 virus Diarrhea 42% 31% 17% COVID-19 13% 16% 12% Upper respiratory tract infection 13% 11% 10% Depression 2 12% 11% 10% Weight decreased 11% 10% 8% Decreased appetite 9% 9% 5% Nausea 8% 9% 7% Fatigue 7% 8% 6% Headache 7% 6% 5% Vomiting 6% 5% 5% Back pain 6% 5% 4% Dizziness 5% 6% 5% Specific Adverse Reactions of JASCAYD for IPF with or without Concomitant Use of Nintedanib or Pirfenidone Diarrhea Diarrhea was more common in patients using JASCAYD with concomitant nintedanib. In patients taking nintedanib, diarrhea occurred in 62%, 50%, and 28% of patients treated with JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, diarrhea occurred in 24% and 8% of patients treated with JASCAYD 18 mg twice daily and placebo, respectively. In patients without concomitant antifibrotic treatment, diarrhea occurred in 26%, 17%, and 8% of patients using JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively. Diarrhea was the most common adverse reaction associated with treatment discontinuation, and most common with JASCAYD used concomitantly with nintedanib: discontinuation occurred in 13%, 2%, and 1% of patients treated with JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily and placebo, respectively. No treatment discontinuations due to diarrhea occurred in patients treated with background pirfenidone and JASCAYD 18 mg twice daily or background pirfenidone with placebo. Diarrhea leading to treatment discontinuation occurred in 1% of patients treated with JASCAYD 18 mg twice daily and in no patients treated with JASCAYD 9 mg or placebo without concomitant antifibrotic tre…