JASCAYD Film-coated tablet Ref.[116755] Active ingredients: Nerandomilast

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

Strong or moderate CYP3A inducers

Pirfenidone

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.

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:

^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):

^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.

Not applicable.