JASCAYD Film-coated tablet Ref.[116083] Active ingredients: Nerandomilast

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.

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)]. 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 Patients¹ with IPF (FIBRONEER-IPF Trial):

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

Specific Adverse Reactions of JASCAYD 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 treatment.

In most patients treated with JASCAYD, diarrhea was of mild to moderate intensity and generally occurred within the first 3 months of treatment.

Weight Decrease

Weight decrease was most common in patients who received JASCAYD concomitantly with nintedanib in the studied population: in patients taking nintedanib, weight decrease occurred in 16%, 14%, and 12% of patients treated with JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, weight decrease occurred in 6% and 5% of patients treated with JASCAYD 18 mg twice daily and placebo, respectively. In patients without background antifibrotic therapy, weight decrease occurred in 8%, 2%, and 6% of patients treated with JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively.

Decreased Appetite

In patients taking nintedanib, decreased appetite occurred in 7%, 10%, and 4% in JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively. In patients using concomitant pirfenidone, decreased appetite occurred in 13% and 10% of patients treated with JASCAYD 18 mg twice daily and placebo, respectively. In patients without concomitant antifibrotic treatment, decreased appetite occurred in 9%, 6%, and 0% of patients treated with JASCAYD 18 mg twice daily, JASCAYD 9 mg twice daily, and placebo, respectively.

Less Common Adverse Reactions

Less common adverse reactions in the studied population following administration of JASCAYD included asthenia (5% JASCAYD 18 mg twice daily, 4% JASCAYD 9 mg twice daily, and 2% placebo), amylase increased (1% JASCAYD 18 mg twice daily, 1% JASCAYD 9 mg twice daily, and 0% placebo), and vasculitis (1% JASCAYD 18 mg twice daily, 1% JASCAYD 9 mg twice daily, and 0% placebo).

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 in patients with IPF [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)].

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 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 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 24 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).

Risk Summary

There are no data on the presence of nerandomilast or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Nerandomilast is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for JASCAYD and any potential adverse effects on the breastfed infant from JASCAYD or from the underlying maternal condition.

Data

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 was present in the plasma of rat pups during the lactation period. In a single dose milk secretion study in lactating rats dosed with radiolabeled nerandomilast by the oral route, similar concentrations of total radioactivity were observed in the milk and plasma of lactating females, with the maximum radioactive concentration observed at 1 hour post dose that was significantly reduced by 24 hours post dose. The concentration of total radioactivity in animal milk does not necessarily predict the concentration of drug in human milk.

The safety and effectiveness of JASCAYD for the treatment of idiopathic pulmonary fibrosis have not been established in pediatric patients.

There were 930 patients 65 years of age and older in the FIBRONEER-IPF trial [see Clinical Studies (14)]. Of the total number of JASCAYD-treated patients in this trial, 623 (79%) were 65 years of age and older, while 251 (32%) were 75 years of age and older. No overall differences in safety or effectiveness of JASCAYD have been observed between patients 65 years of age and older and younger adult patients.

JASCAYD has not been investigated in patients with end stage renal disease (eGFR <15 mL/min/1.73 m²). Use of JASCAYD is not recommended in patients with end stage renal disease (eGFR <15 mL/min/1.73 m²).

The recommended dosage in patients with mild (eGFR ≥60 to <90 mL/min/1.73 m² according to CKD-EPI), moderate (eGFR ≥30 to <60 mL/min/1.73 m²), or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m²) is the same as that in patients with normal renal function [see Clinical Pharmacology (12.3)].

JASCAYD has not been investigated in patients with severe (Child-Pugh Class C) hepatic impairment. Use of JASCAYD is not recommended in patients with severe (Child-Pugh Class C) hepatic impairment.

The recommended dosage in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment is the same as that in patients with normal hepatic function [see Clinical Pharmacology (12.3)].