IQIRVO Film-coated tablet Ref.[113546] Active ingredients: Elafibranor

Liver related events

Increases in liver biochemical tests including transaminases and bilirubin levels have been reported in participants receiving elafibranor.

Clinical and laboratory assessment of liver function should be done prior to initiation of elafibranor treatment and thereafter according to routine patient management.

If increases in liver biochemical tests and/or liver dysfunction are observed, prompt investigation of the cause is recommended and interruption of elafibranor treatment should be considered.

Elevated blood creatine phosphokinase and muscle injury

Increases in blood creatine phosphokinase (CPK) have been reported in participants receiving elafibranor (see section 4.8). CPK should be evaluated prior to initiation of elafibranor treatment and thereafter according to routine patient management. Periodic CPK measurements may be considered in patients starting elafibranor treatment, especially those on concomitant HMG-CoA reductase inhibitors. If increases in CPK or unexplained signs and symptoms of muscle injury are observed, prompt investigation of the cause is recommended and interruption of elafibranor treatment should be considered (see section 4.8).

Embryo-foetal toxicity

Based on data from animal studies, elafibranor is suspected to cause congenital malformations and reduced foetal survival when administered to a pregnant woman (see section 4.6). Therefore, elafibranor is contra-indicated in women with a known or suspected pregnancy and in women of childbearing age who do not use effective contraception (see sections 4.3, 4.5 and 4.6). Women with childbearing potential should be informed about this.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Effect of elafibranor on other medicinal products

CYP3A4 substrates

Based on clinical studies conducted, elafibranor may be a mild CYP3A4 inducer. A clinical interaction study demonstrated that co-administration of elafibranor 80 mg once daily at steady state and a single dose of combined oral contraceptive (0.02 mg ethinylestradiol and 0.15 mg levonorgestrel) produced a decrease of ethinylestradiol exposure (C_max decreased by 20% and AUC_inf decreased by 35%) which may lead to contraceptive failure and/or an increase in breakthrough bleeding, while levonorgestrel exposure remained unaffected. As a result, women of childbearing potential should use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives (see section 4.6).

CYP2C9 substrates (Warfarin)

Concomitant administration of elafibranor with warfarin resulted in no increase in exposure (AUC, C_max) of warfarin, and no difference in international normalized ratio (INR) compared to warfarin alone.

CYP3A, Breast Cancer Resistance Protein (BCRP), organic anion transporting polypeptides 1B1 (OATP1B1) and OATP1B3 substrates (Simvastatin) and CYP3A, organic anion transporting polypeptides 1B1 (OATP1B1) and OATP1B3 substrates (Atorvastatin)

Concomitant administration of repeat doses of elafibranor with simvastatin, or atorvastatin, resulted in no clinically meaningful change in exposure of simvastatin or its β-Hydroxyacid metabolite, or atorvastatin.

The C_max and AUC_inf of the active metabolite of simvastatin, simavastatin β-hydroxyacid, decreased by 26% and 32% respectively following concomitant use of a single dose of simvastatin 20 mg and elafibranor 80 mg once daily at steady state.

The C_max and AUC_inf of atorvastatin decreased by 28% and 11% respectively following concomitant use of a single dose of atorvastatin 40 mg and elafibranor 180 mg once daily at steady state.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors (Sitagliptin)

No clinically significant effects on blood levels of GLP-1 were observed when co- administering 100 mg of elafibranor as a DDI perpetrator once daily for 15 days with a single oral 100 mg dose of sitagliptin during a meal test.

Fertility

No human data on the effect of elafibranor on fertility are available. Animal studies do not indicate any direct or indirect effects on fertility or the ability to reproduce (see section 5.3).

Women of childbearing potential/contraception

Women of childbearing potential have to use effective contraception during and up to at least 3 weeks following the final dose of elafibranor. Elafibranor may decrease ethinylestradiol-containing contraceptives efficacy (see section 4.5), and therefore women of childbearing potential should use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives. The pregnancy status of patients of childbearing potential should be checked prior to initiation of elafibranor treatment (see section 4.4).

Pregnancy

There is limited amount of data from the use of elafibranor in pregnant women. Studies in pregnant animals with elafibranor have shown reproductive toxicity (foetal loss, malformations, stillbirths and/or perinatal deaths) at clinically relevant exposure (see sections 4.4 and 5.3).

Elafibranor is contraindicated during pregnancy (see section 4.3). If a patient becomes pregnant, treatment with elafibranor should be discontinued.

Lactation

It is unknown whether elafibranor or its metabolites are excreted in human milk. There is no information on the excretion of elafibranor or its metabolites in animal milk, but adverse effects were seen in offspring when elafibranor was administered to female rats during pregnancy (see section 5.3) and lactation at clinically relevant exposure.

A risk to the suckling child cannot be excluded.

Elafibranor should not be used during breastfeeding and for at least 3 weeks following last dose of elafibranor.

Elafibranor has no influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse drug reactions associated with elafibranor treatment (n=108) which occurred in more than 10% of participants and with a higher incidence than in the placebo group (n=53; difference >1%) were abdominal pain (11.1% versus 5.7%), diarrhoea (11.1% versus 9.4%), nausea (11.1% versus 5.7%), and vomiting (11.1% versus 1.9%). These were non-serious, mild to moderate, occurred early in treatment and tended to resolve within days to a few weeks without any dose modification or supportive measures.

The most common adverse drug reaction leading to treatment discontinuation was blood CPK increased (3.7%).

Tabulated list of adverse reactions

Within the system organ class, the adverse reactions are listed by frequency using the following categories: 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).

^a includes abdominal pain upper and abdominal pain lower

Description of selected adverse reactions

Headache

In the pivotal phase 3 ELATIVE study, 9 (8.3%) participants in the elafibranor group and 6 (11.3%) participants in the placebo group experienced headache. However, within the first 10 days of study treatment, more participants in the elafibranor group experienced headache compared to the placebo group (3.7% compared to 0% respectively).

Blood CPK increased

In the pivotal phase 3 ELATIVE study, 4 (3.7%) participants in the elafibranor group and no participants in the placebo group had clinically significant blood CPK increase, leading to drug discontinuation. In 2 of the 4 participants, the CPK was >5 x upper limit of normal (ULN). All events were non-serious and mild to moderate in intensity. Two of the participants also experienced associated symptom of myalgia. At baseline, mean CPK values were similar between the treatment groups and within normal range; values at week 52 remained within normal range in both groups. The mean (standard deviation) change from baseline at week 52 was 6.2 (38.1) U/L in the elafibranor group and 12.3 (67.0) U/L in the placebo group.

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.