nerandomilast: prescribing information – dosing, contraindications, interactions, side effects

Jascayd is indicated for the treatment of adult patients with Idiopathic Pulmonary Fibrosis (IPF).
Jascayd is indicated for the treatment of adult patients with Progressive Pulmonary Fibrosis (PPF).

Treatment should be initiated by physicians experienced in the management of diseases for which Jascayd is approved.
Posology
The recommended dose is 18 mg twice daily, administered approximately 12 hours apart.
Based on individual patient tolerability of the side effects of diarrhoea or weight decrease (see section 4.4 and section 4.8) and based on the anticipated benefit of treatment with nerandomilast (see section 5.1), the dose may be reduced to 9 mg twice daily (except in patients who concomitantly use pirfenidone or strong or moderate cytochrome P450 3A (CYP3A) inducers, see section 4.5). Once the adverse reaction has resolved or is adequately controlled, treatment may be resumed at the recommended dose of 18 mg twice daily.
Concomitant use with strong CYP3A inhibitors
If used concomitantly with strong CYP3A inhibitors, the dose must be reduced to 9 mg twice daily (see section 4.5).
Concomitant use with strong or moderate CYP3A inducers
If used concomitantly with strong or moderate CYP3A inducers, the recommended dose is 18 mg twice daily and must not be reduced to 9 mg twice daily (see section 4.5).
Concomitant use with pirfenidone
Concomitant use with pirfenidone decreased nerandomilast exposure by approximately 50% (see section 4.5). In patients using pirfenidone, the recommended dose is 18 mg twice daily and must not be reduced to 9 mg twice daily.
Missed dose
If a dose is missed, the next dose should be taken at the next scheduled time.
The patient should not take an additional dose. The recommended maximum dose of 18 mg twice daily should not be exceeded.
Special populations
Elderly
No dose adjustment is required in elderly patients (see section 5.2).
Renal impairment
No dose adjustment is necessary in patients with mild, moderate, or severe renal impairment (eGFR ≥ 15 and < 90 mL/min, based on CKD-EPI formula) (see section 5.2).
Treatment of patients with end stage renal disease (eGFR < 15 mL/min) is not recommended. The pharmacokinetics, safety and efficacy of nerandomilast in these patients have not been investigated.
Hepatic impairment
No dose adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment (see section 5.2).

Treatment of patients with severe hepatic impairment (Child-Pugh class C) is not recommended. The pharmacokinetics, safety and efficacy of nerandomilast in these patients have not been investigated.
Paediatric population
The safety and efficacy in paediatric patients have not yet been established.
No data are available.
Method of administration
Jascayd is for oral use. The tablets should be swallowed whole with water.
Jascayd can be taken with or without food (see section 5.2).
Alternative method of administration
For patients who have difficulty swallowing the whole tablet, a tablet may be dispersed in a glass with approximately 100 mL of non-carbonated, room temperature drinking water. No other liquids should be used. The tablet should be dropped in water without crushing it and stirred regularly for approximately 15-20 min until the tablet is dispersed into very small pieces (the tablets will not completely dissolve). The resultant dispersion should be drunk within 2 hours of mixing. If the dispersion is not drunk immediately, patients must stir again before drinking. The glass should be rinsed with approximately 100 mL of water which should also be drunk to ensure the full dose is administered.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile
The most frequent adverse reactions are diarrhoea and weight decreased.
Tabulated list of adverse reactions
Table 1 shows the frequencies of adverse reactions based on 52-week data from two randomised, placebo-controlled, double-blind Phase III clinical trials (FIBRONEER-IPF in IPF and FIBRONEER-ILD in PPF) with twice daily nerandomilast doses of 9 mg or 18 mg. Adverse reactions are listed by MedDRA System Organ Class (SOC).
Frequencies are defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).
Table 1. Adverse reactions
System Organ Class
Adverse reactions
Frequency category
IPFb
PPF
Metabolism and nutrition disorders
Decreased appetite
Common
Common
Gastrointestinal disorders
Diarrhoeaa
Very common
Very common
Nausea
Common
Common
Musculoskeletal and connective tissue disorders
Back pain
Common
Common
Investigations
Weight decreaseda
Common
Common a see section Description of selected adverse reactions b Frequencies were calculated excluding patients in the 9 mg dose group receiving concomitantly pirfenidone, as this combination is not recommended due to a clinically relevant drug-drug interaction (see section 4.2 and section 4.5).
Description of selected adverse reactions
Diarrhoea
In most patients treated with nerandomilast, diarrhoea was of mild to moderate intensity and generally occurred within the first 3 months of treatment.
Most cases were managed with symptomatic therapy with anti-diarrhoeal medication and, if applicable, with reduction in background therapy with nintedanib or pirfenidone.
Severe diarrhoea has been reported more frequently in patients receiving nerandomilast in combination with nintedanib.

The frequency of diarrhoea depended on the presence and type of background treatment (see Table 2).
Table 2. Frequencies of diarrhoea by background treatment subgroups over 52 weeks in the FIBRONEER-IPF trial (patients with IPF) and the FIBRONEER-ILD trial (patients with PPF).

IPF (FIBRONEER-IPF)
PPF (FIBRONEER-ILD)

Placeb o
Nerandomilas t
9 mg bid
Nerandomilas t
18 mg bid
Placeb o
Nerandomilas t
9 mg bid
Nerandomilas t
18 mg bid
No backgroun d treatment
8%
17%
26%
16%
15%
27%
Nintedanib backgroun d therapy
27%
49%
62%
36%
48%
49%
Pirfenidon e backgroun d therapy
8% n.a.a
23% n.a.b n.a.b n.a.b a Not applicable, as 9 mg bid nerandomilast is not a recommended dose for patients receiving pirfenidone.
b Not applicable, as pirfenidone was not permitted as background treatment in FIBRONEER-ILD.
bid = twice daily
IPF
In patients treated in the FIBRONEER-IPF trial, without background IPF treatment, severe diarrhoea was not reported; with background nintedanib, it was reported in 5% in 18 mg, 2% in 9 mg and < 1% in placebo; with background pirfenidone, it was not reported.
Diarrhoea was the most common adverse reaction associated with treatment discontinuation and occurred most frequently with background nintedanib. Without background IPF treatment, discontinuations occurred in 1% in 18 mg and were not reported in 9 mg or placebo; with background nintedanib, in 13% in 18 mg, 2% in 9 mg and 1% in placebo; with background pirfenidone, no treatment discontinuations were reported in 18 mg or placebo.
PPF
In patients treated in the FIBRONEER-ILD trial, without background nintedanib treatment, severe diarrhoea was not reported; with background nintedanib, it was reported in 2% in 18 mg, 1% in 9 mg and < 1% in placebo.
Diarrhoea was the most common adverse reaction associated with treatment discontinuation and occurred most frequently with background nintedanib. Without background nintedanib treatment, discontinuations occurred in 1% in 18 mg and were not reported in 9 mg or placebo; with background nintedanib, in 4% in 18 mg, 3% in 9 mg and 1% in placebo.
Weight decrease
In clinical trials, weight decrease started after the second week of treatment and stabilised after 12 weeks of treatment.

IPF
In the FIBRONEER-IPF trial, the mean absolute change in body weight from baseline to week 52 was -2.6 kg for patients treated with nerandomilast 18 mg, -2.4 kg for patients treated with nerandomilast 9 mg, and -1.8 kg for patients receiving placebo.
The frequency of weight decrease depended on the presence and type of background IPF treatment:
without background IPF treatment, 7% in 18 mg, 1% in 9 mg, and 6% in placebo; with background nintedanib, 16% in 18 mg, 13% in 9 mg and 11% in placebo; with background pirfenidone, 5% in 18 mg and in placebo.
PPF
In the FIBRONEER-ILD trial, the mean absolute change in body weight from baseline to week 52 was -3.2 kg for patients treated with nerandomilast 18 mg, -2.0 kg for patients treated with nerandomilast 9 mg and -2.0 kg for patients receiving placebo.
The frequency of weight decrease depended on the presence or absence of background nintedanib treatment: without background nintedanib, 10% in 18 mg, 5% in 9 mg and 4% in placebo; with background nintedanib, 11% in 18 mg, 9% in 9 mg and 8% in placebo.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Diarrhoea, nausea and decreased appetite
In clinical trials, diarrhoea, nausea and decreased appetite were frequently reported adverse reactions (see section 4.8) particularly in patients receiving nerandomilast in combination with nintedanib or pirfenidone. In most patients, these adverse reactions were of mild to moderate intensity. Patients should be monitored and adverse reactions managed with adequate symptomatic treatments such as hydration and anti-diarrhoeal or anti-emetic medicinal products, as applicable. Reduction in background therapy with nintedanib or pirfenidone should be managed in line with the advice in the respective SmPCs. Caution is advised in patients who are debilitated, have existing gastrointestinal symptoms, or have previously experienced significant gastrointestinal adverse reactions with nintedanib or pirfenidone. If patients with severe or persistent diarrhoea, nausea or decreased appetite do not respond to symptomatic treatment, dose reduction (see section 4.2) or treatment interruption, nerandomilast treatment should be discontinued.
Weight decrease
Treatment with nerandomilast has been associated with dose dependent weight loss particularly with concomitant use of nintedanib. Body weight should be monitored regularly during therapy. If unexplained weight loss becomes progressive or clinically concerning, treatment should be reassessed and dose reduction or discontinuation of treatment should be considered. Nerandomilast should be used with caution in patients who are underweight or have conditions in which additional weight loss may be medically undesirable (see section 4.8).

Psychiatric disorders
Psychiatric disorders can be a common comorbidity in patients with IPF and PPF. Psychiatric events, including very rare instances of suicidal ideation and behaviour, have been reported in clinical studies of nerandomilast across treatment groups. Routine monitoring for psychiatric disorders is recommended.
Excipients with known effect
Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

Based on in vitro assessment, nerandomilast is mainly metabolised by CYP3A and is a substrate of P-glycoprotein (P-gp).
Effects of other products on nerandomilast
Strong CYP3A inhibitors
Clinical
Impact:
When a single dose of 6 mg nerandomilast was co-administered with multiple doses of itraconazole (a dual strong inhibitor of CYP3A and P-gp) in healthy volunteers, the exposure of nerandomilast increased by 2.2-times for AUC and by 1.3-times for Cmax.
Intervention:
If used concomitantly with strong CYP3A inhibitors, the dose must be reduced to
9 mg twice daily (see section 4.2).
Examples:
Clarithromycin, itraconazole, ritonavir
Strong or moderate CYP3A inducers
Clinical
Impact:
When a single dose of 18 mg nerandomilast was co-administered with multiple doses of carbamazepine (a strong CYP3A inducer) in healthy volunteers, the exposure of nerandomilast decreased by 51% for AUC and by 31% for Cmax.
When a single dose of 18 mg nerandomilast was co-administered with multiple doses of bosentan (a moderate CYP3A inducer) in healthy volunteers, the exposure of nerandomilast decreased by 41% for AUC and by 15% for Cmax.
Intervention:
If used concomitantly with strong or moderate CYP3A inducers, the recommended dose is 18 mg twice daily and must not be reduced to 9 mg twice daily (see section 4.2).
Examples:
Carbamazepine, St. John’s wort, rifampicin, phenytoin, bosentan, metamizole
Pirfenidone
Clinical
Impact:
Concomitant use with pirfenidone decreased exposure of nerandomilast by approximately 50%, based on Ctrough,ss observed in the phase 3 study in patients with

IPF. Based on in vitro data, pirfenidone may induce CYP3A activity, leading to decreased nerandomilast exposure. When nerandomilast was co-administered with pirfenidone in patients with IPF in this phase 3 trial, efficacy was not observed at the 9 mg dose but a reduction in Forced Vital Capacity (FVC) decline was observed with the 18 mg dose (see section 5.1).
Intervention:
In patients using pirfenidone, the recommended dose is 18 mg twice daily and must not be reduced to 9 mg twice daily (see section 4.2).
Nintedanib
Concomitant use with nintedanib did not alter the exposure of nerandomilast based on trough concentrations at steady state.
Effects of nerandomilast on other products
No clinically relevant differences in the pharmacokinetics of the following active substances were observed when used concomitantly with nerandomilast: pirfenidone, nintedanib, and oral midazolam (CYP3A4 substrate). Based on the results for concomitant use with midazolam, nerandomilast is not expected to decrease or increase the systemic exposure of other medicinal products that are mainly metabolised by CYP3A, e.g., oral contraceptives.

Contraception
Based on findings in animal studies, nerandomilast may cause loss of pregnancy (see section Pregnancy below and section 5.3).
Women of childbearing potential should be advised to avoid becoming pregnant and to use effective contraceptive methods during treatment.
Pregnancy
There are no data from the use of nerandomilast in pregnant women. Based on findings in animal studies, nerandomilast may cause loss of pregnancy (see section 5.3).
Women of childbearing potential should be advised to avoid becoming pregnant while taking Jascayd.
Jascayd is not recommended during pregnancy and in women of childbearing potential not using contraception.
Female patients should be advised to notify their health care provider if they become pregnant or suspect they may be pregnant during therapy with Jascayd. Pregnant women and women of childbearing potential should be advised of the potential risk of foetal loss.
Breast-feeding
There are no data on the presence of nerandomilast in human milk or its effects on either the breast-fed child or on milk production. Studies in rats have shown evidence of excretion of nerandomilast in milk (see section 5.3).
A risk to the breast-fed infant cannot be excluded. Breast-feeding should be discontinued during treatment with Jascayd.

Fertility
There are no data on the impact of nerandomilast on human fertility. No adverse effects on fertility were observed in male and female rats at 4-times human exposure (see section 5.3).

Jascayd has no or negligible influence on the ability to drive and use machines.

Symptoms
In clinical trials, single doses of up to 48 mg of nerandomilast were studied in healthy volunteers without evidence of dose limiting toxicities. Cases of accidental overdose were reported in patients who received doses up to 72 mg/day for up to 17 days.
The observed adverse reactions were consistent with the known safety profile of nerandomilast.
Therapy
In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment is provided.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA61
Mechanism of action
Nerandomilast is a selective inhibitor of phosphodiesterase 4 (PDE4) with preferential inhibition of the PDE4B isoenzyme over PDE4A, C and D. There is a 9-fold selectivity over PDE4D, 24-fold selectivity over PDE4A and 870-fold selectivity over PDE4C based on in vitro data. At the recommended doses, inhibition of PDE4B and weaker inhibition of PDE4D can be expected. PDE4 hydrolyses and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both anti-

fibrotic and immunomodulatory effects as preferential PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of pro-fibrotic growth factors and inflammatory cytokines, which are overexpressed in fibrotic lung disease.
Pharmacodynamic effects
Cardiac electrophysiology
At single doses of nerandomilast up to 48 mg (2.2-times the estimated Cmax,ss exposure at the maximum recommended human dose), clinically significant QTc interval prolongation was not observed.
Clinical efficacy and safety
Idiopathic Pulmonary Fibrosis (IPF)
A randomised, double-blind, placebo-controlled trial (FIBRONEER-IPF) evaluated the clinical efficacy and safety of nerandomilast in adult patients with IPF with or without receiving background treatment of nintedanib or pirfenidone. Patients were required to have a Forced Vital Capacity (FVC) greater than or equal to 45% of predicted and a diffusing capacity of the lungs for carbon monoxide (DLCO) greater than or equal to 25% of predicted normal corrected for haemoglobin (Hb).
1 177 patients were randomised in a 1:1:1 ratio to receive nerandomilast 9 mg twice daily, nerandomilast 18 mg twice daily, or placebo twice daily for at least 52 weeks. Randomisation was stratified by the presence of nintedanib or pirfenidone versus the absence of these background treatments at baseline. The primary endpoint of the trial was the absolute change from baseline in FVC in mL at 52 weeks compared with placebo. The key secondary endpoint was the time to the first occurrence of any of the components of the composite endpoint: first acute IPF exacerbation, first hospitalisation for respiratory cause, or death over the duration of the trial. Patients were followed for a median time of 14.6 months at the time of main analysis and 17.0 months at the end-of-trial analysis.

The pharmacokinetics of nerandomilast have been characterised in healthy volunteers, patients with IPF and patients with PPF. No clinically relevant differences in pharmacokinetics of nerandomilast were noted between these populations.
Absorption
Nerandomilast reached peak plasma concentrations (Cmax) at a median time (Tmax) of 1.00-1.25 h (range between 0.5-4 hours) after oral administration of 9 mg and 18 mg doses. The absolute oral bioavailability of nerandomilast was 73% (90% CI: 67-79%).
Administration of 18 mg nerandomilast with a high-fat and high caloric meal did not change nerandomilast exposure to a clinically relevant extent (AUC increased by approximately 15% while Cmax decreased by approximately 14%).
Distribution
After single intravenous administration of nerandomilast, the geometric mean volume of distribution Vss was approximately 94 L (gCV 32.0%). In vitro, nerandomilast was a substrate of the transporter protein P-gp, but not of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.
In vitro human plasma protein binding of nerandomilast was 77% with no concentration dependence.
In healthy volunteers, nerandomilast was preferentially distributed in plasma with a blood-to-plasma ratio of 0.6-0.8.
Biotransformation
Nerandomilast is mainly metabolised via oxidation by CYP3A and glucuronidation by multiple uridine-5′-diphospho-glucuronosyltransferase enzymes.
Following single oral administration, nerandomilast was the primary circulating component representing approximately 50% of circulating radioactivity.
After multiple oral administrations of 12 mg nerandomilast twice daily, the only major metabolite identified in plasma at steady state was the di-oxidative metabolite BI 764333/M480(4). This pharmacologically inactive metabolite represented 12% of the total plasma material at steady state consisting of both parent compound and all its metabolites.