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JASCAYD (nerandomilast tablets), for oral administration, contain nerandomilast, a phosphodiesterase 4 (PDE4) inhibitor. The chemical name of nerandomilast is [1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)-1-piperidyl]- 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol. Nerandomilast has one chiral center and is the R-stereoisomer. Its structural formula is:
 |
Nerandomilast is a white to off-white to light yellow powder with an empirical formula of C20H25ClN6O2S and a molecular weight of 449 g/mol. At or below pH 3, nerandomilast is very slightly to slightly soluble in water, and above pH 3 it is practically insoluble.
Each film-coated tablet of JASCAYD contains 9 mg or 18 mg of nerandomilast and the following inactive ingredients: croscarmellose sodium, ferric oxide red (18 mg tablets only), ferric oxide yellow (9 mg tablets only), ferrosoferric oxide (18 mg tablets only), hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, and talc. Each JASCAYD tablet contains less than 5 mg of sodium.
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)
|
JASCAYD |
JASCAYD |
Placebo |
|
|
Diarrhea |
42% |
31% |
17% |
|
COVID-19 |
13% |
16% |
12% |
|
Upper respiratory tract infection |
13% |
11% |
10% |
|
Depression2 |
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% |
|
1Studied population including patients who received JASCAYD with or without background antifibrotic treatment (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 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).
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)].
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)].
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)].
Included as part of the PRECAUTIONS section.
No information provided.
The carcinogenic potential of nerandomilast was assessed in Tg.rasH2 mice and Wistar Han rats. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice that received nerandomilast for 26 weeks at oral doses up to 60 and 100 mg/kg/day, respectively. No evidence of tumorigenicity was observed in male or female rats that received nerandomilast for up to 102 weeks at oral doses up to 2 mg/kg/day (approximately 2 times the MRHD on an AUC basis).
Nerandomilast was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat micronucleus assay.
Nerandomilast had no effect on fertility in male or female rats at oral doses up to 6 mg/kg/day (approximately 3 or 4 times the MRHD on an AUC basis, respectively). Decreased mating, pregnancy, and fertility indices at the highest tested dose of 9 mg/kg/day (approximately 4 or 9 times the MRHD on an AUC basis) were attributed to excessive general toxicity.
Sexually mature female monkeys administered nerandomilast by the oral route for 39 weeks showed sporadic menstrual cycle prolongation at dose levels of 10 mg/kg/day and 30 mg/kg/day (approximately 3- and 10 times the MRHD on an AUC basis, respectively). Menstrual cycles were not affected in monkeys at oral doses of 3 mg/kg/day (equivalent to the MRHD on an AUC basis).
In the event of an overdosage with JASCAYD, monitor the patient for any signs or symptoms of adverse reactions and provide appropriate symptomatic treatment. Consider contacting the Poison Help line (1-800-222- 1222) or a medical toxicologist for additional overdosage management recommendations.
No information provided.
Nerandomilast is an inhibitor of phosphodiesterase 4 (PDE4) with at least nine-fold preferential inhibition of the PDE4B isoenzyme over PDE4A, PDE4C and PDE4D based on in vitro data. PDE4 hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both anti-fibrotic and immunomodulatory effects as PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of pro-fibrotic growth factors and inflammatory cytokines, which are overexpressed in IPF.
Increases in nerandomilast steady state trough concentrations were associated with better efficacy, as indicated by a smaller reduction in forced vital capacity (FVC) from baseline over 52 weeks.
At 2.1 times the maximal concentration provided by the maximum recommended dose of nerandomilast, clinically significant QTc interval prolongation was not observed.
Nerandomilast exposure increased in a dose proportional manner following administration of single doses of 0.0032 to 2.6 times a single dose of 18 mg and multiple doses of 0.056 to 1 times the maximum recommended dose of 18 mg twice daily. Following administration of multiple doses of 18 mg twice daily, Cmax increases 1.3- fold and AUCtau increases 1.38-fold. Nerandomilast steady state is reached in approximately 4 days.
No clinically relevant differences in nerandomilast pharmacokinetics were observed between healthy subjects and patients with IPF.
The absolute oral bioavailability of nerandomilast is 73%. Nerandomilast median (min, max) time to maximum plasma concentration (Tmax) is 1 to 1.25 hours (range 0.5 to 4 hours).
Effect of Food
No clinically relevant differences in nerandomilast pharmacokinetics were observed following administration with a high-fat meal (1000 calories, 50% fat).
Nerandomilast steady state apparent (oral) central volume of distribution is 93 L (CV 37%). In vitro, nerandomilast plasma protein binding is 77% and is not concentration dependent. Nerandomilast blood-to- plasma ratio is approximately 0.6 to 0.8.
The geometric mean (CV%) elimination half-life of nerandomilast is 17 hours (46%) with an apparent (oral) clearance of 15.2 L/h.
Metabolism
Nerandomilast is primarily metabolized by CYP3A and to a lesser extent by multiple UGT enzymes.
After oral administration of nerandomilast, chiral inversion from the pharmacologically active R-enantiomer to the pharmacologically inactive S-enantiomer occurs via metabolism. The S-enantiomer was identified as a minor metabolite of nerandomilast. The R-enantiomer is the predominant circulating enantiomer.
Excretion
After a single oral dose of radiolabeled nerandomilast, approximately 58% of the dose was recovered in feces (14% as unchanged nerandomilast) and 36% of the dose was recovered in urine (13% as unchanged nerandomilast).
No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (range: 18 to 90 years), body weight (range: 34 to 136 kg), sex, race (66% White and 32.5% Asian), mild (eGFR ≥60 to <90 mL/min/1.73 m2 [calculated according to Chronic Kidney Disease Epidemiology Collaboration]), moderate (eGFR ≥30 to <60 mL/min/1.73 m2), or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m2), or mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Subjects with end stage renal disease or severe hepatic impairment (Child-Pugh Class C) have not been studied [see Use in Specific Populations (8.6, 8.7)].
Strong CYP3A Inhibitors: Nerandomilast Cmax increased by 1.3-fold and AUC increased by 2.2-fold following concomitant administration with itraconazole (a strong CYP3A and P-gp inhibitor) 200 mg oral solution once daily for 4 days [see Drug Interactions (7.1)].
Pirfenidone: Nerandomilast trough concentrations at steady state (Ctrough,ss) decreased by approximately 50% following concomitant administration with pirfenidone in patients with IPF [see Drug Interactions (7.1)].
Other Drugs: No clinically significant differences in nerandomilast Ctrough,ss were observed when used concomitantly with nintedanib. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with nerandomilast: oral midazolam (CYP3A4 substrate), pirfenidone, and nintedanib.
In Vitro Studies
CYP450 Enzymes: Nerandomilast is a CYP3A4 substrate. Nerandomilast does not inhibit CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
Transporter Systems: Nerandomilast is a P-glycoprotein (P-gp) substrate, but is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2. Nerandomilast is an inhibitor of P-gp, MATE1, MATE2-K, but is not expected to cause clinically significant interactions. Nerandomilast is not an inhibitor of BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise female patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant during treatment with JASCAYD. Advise female patients of the potential risk of fetal loss [see Use in Specific Populations (8.1)].
Inform patients that if they miss a dose of JASCAYD, they should take the next dose at the next scheduled time. Advise patients to not make up for a missed dose or exceed the recommended dosage of 18 mg twice daily [see Dosage and Administration (2.1)].
Distributed by:
Boehringer Ingelheim Pharmaceuticals,
Inc. Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH,
Ingelheim, Germany
JASCAYD is a trademark of and used under license from Boehringer Ingelheim International GmbH. Copyright 2025 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED COL11694AJ032025
