Nerandomilast

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.

If used concomitantly with strong CYP3A inhibitors, the dose must be reduced to 9 mg twice daily.

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.

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.

Concomitant use with pirfenidone decreased nerandomilast exposure by approximately 50%. In patients using pirfenidone, the recommended dose is 18 mg twice daily and must not be reduced to 9 mg twice daily.

There are no data from the use of nerandomilast in pregnant women. Based on findings in animal studies, nerandomilast may cause loss of pregnancy.

Women of childbearing potential should be advised to avoid becoming pregnant while taking nerandomilast. Nerandomilast 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 nerandomilast. Pregnant women and women of childbearing potential should be advised of the potential risk of foetal loss.

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.

A risk to the breast-fed infant cannot be excluded. Breast-feeding should be discontinued during treatment with nerandomilast.

Contraception

Based on findings in animal studies, nerandomilast may cause loss of pregnancy.

Women of childbearing potential should be advised to avoid becoming pregnant and to use effective contraceptive methods during treatment.

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.

Nerandomilast 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.

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.