Elafibranor

The safety and efficacy of elafibranor have not been established in patients with PBC with severe hepatic impairment. Use in patients with severe hepatic impairment (Child-Pugh C) is not recommended.

CPK elevation and/or myalgia occurred in patients on elafibranor monotherapy. Co-administration of elafibranor and HMG-CoA reductase inhibitors (statins) which have a risk of myalgia, can increase the risk of myopathy by a mechanism that has not been fully characterized.

Monitor for signs and symptoms of muscle injury. Consider periodic assessment (clinical exam, CPK) during treatment. Interrupt elafibranor treatment if there is new onset or worsening of muscle pain or myopathy.

Bile acid sequestrants may interfere with the action of elafibranor by reducing its absorption and systemic exposure, which may reduce elafibranor efficacy.

Administer elafibranor at least 4 hours before or 4 hours after taking a bile acid binding sequestrant, or at as great an interval as possible.

Elafibranor is a weak CYP3A4 inducer. Co-administration of elafibranor and hormonal contraceptives (e.g., birth control pills, skin patches, implant) may reduce the systemic exposure of progestin and ethinyl estradiol (CYP3A4 substrates), which may lead to contraceptive failure and/or an increase in breakthrough bleeding.

Switch to effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with elafibranor and for at least 3 weeks after last dose.

Co-administration of elafibranor with rifampin, an inducer of metabolizing enzymes, may reduce the systemic exposure of elafibranor and its active metabolite via increased metabolism and may result in delayed or suboptimal biochemical response.

Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during treatment with elafibranor.

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.

Elafibranor is contraindicated during pregnancy. If a patient becomes pregnant, treatment with elafibranor should be discontinued.

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 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.

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.

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. The pregnancy status of patients of childbearing potential should be checked prior to initiation of elafibranor treatment.

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.