4.1. Therapeutic indications

Iqirvo is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

4.2. Posology and method of administration

Posology

The recommended dose is 80 mg once daily with or without food.

Special populations

Elderly patients (65 years of age and above)

No dose adjustment is necessary in patients older than 65 years of age (see section 5.2).

Renal impairment

No dose adjustment is necessary in patients with renal impairment (see section 5.2).

Hepatic impairment

Prior to initiation of treatment with Elafibranor the patient's hepatic status must be known.

No dose adjustment is necessary in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Whether the patient has decompensated cirrhosis (including Child-Pugh C) or has had a prior decompensation event should be determined prior to initiation of treatment because 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 (see section 5.2).

Paediatric population

There is no relevant use of elafibranor in the paediatric population (below 18 years of age) for the indication of PBC.

Missed dose

If a dose of elafibranor is missed, the patient should not take the missed dose and instead take their subsequent dose at the next scheduled time point. The patient should not take a double dose to make up for the missed dose.

Method of administration

For oral use.

Take one tablet once daily. The tablet should not be crushed, chewed or split prior to administration.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Liver related events

Increases in liver biochemical tests including transaminases and bilirubin increase levels have been reported in 3.7% of participants receiving elafibranor compared to 5.7% of participants receiving placebo.

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) (3.7% in elafibranor group compared to 0% in placebo group). In addition to these reported CPK increases, there was one case of rhabdomyolysis which occurred in the pivotal phase 3 ELATIVE study in a participant with cirrhosis and ongoing treatment with an HMG-CoA reductase inhibitor. CPK should be evaluated prior to initiation of elafibranor treatment to determine the baseline CPK level and thereafter, according to the routine patient management. Caution should be used in patients with predisposing factors including old age (>65 years), hypothyroidism, personal or familial history of hereditary muscular disorders, severe infection, trauma, surgery, disturbances of hormone or electrolyte imbalance or alcohol abuse. Periodic CPK measurements may be considered in patients starting elafibranor treatment, especially those on concomitant HMG-CoA reductase inhibitors. Patients on elafibranor treatment should be advised to report promptly any unexplained muscle symptoms such as pain, soreness, or weakness to their treating physician, especially if accompanied by malaise or fever. 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), and levels monitored as per standard medical practise.

Embryo-Foetal Toxicity

Based on data from animal studies, elafibranor may cause foetal harm when administered to a pregnant woman. Patients should be informed of the potential risk to the foetus if elafibranor is taken during pregnancy (see section 4.6).

The use of elafibranor is not recommended during pregnancy and in women of childbearing potential not using effective contraception (see section 4.6). The pregnancy status of women of childbearing potential should be checked prior to initiation of elafibranor treatment.

Women of childbearing potential should be advised to use effective contraception during treatment and for 3 weeks following the final dose of elafibranor.

Hypersensitivity Reactions

If severe hypersensitivity reactions occur, permanently discontinue Iqirvo. If a mild or moderate hypersensitivity reaction occurs, stop Iqirvo and treat promptly then continue with the follow up until resolution of the signs and symptoms.

Fractures

Fractures occurred in 6% of Iqirvo-treated patients compared to no placebo-treated patients.

Consider the risk of fracture in the care of patients treated with Iqirvo and monitor bone health according to current standards of care.

Elderly (over 80 years)

There is no supporting data on using Elafibranor in those over 80 years of age.

Interaction with fibrates

Fibrates and elafibranor act on some similar pathways. Due to the potential for pharmacodynamic interactions and the exclusion of concomitant fibrate use in clinical studies, data on their combined use is limited. Therefore, concomitant administration is not recommended.

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

4.5. Interaction with other medicinal products and other forms of interaction

Based on in vitro and in vivo studies, no clinically relevant drug-drug interaction is expected by co-administering elafibranor with any other medicinal products (see section 5.2).

4.6. Fertility, pregnancy, and lactation

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

Elafibranor is not recommended in women of childbearing potential not using effective contraception because of potential harm to the foetus.

Women of childbearing potential should continue to use effective contraception during and up to at least for 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.

Women planning to become pregnant are recommended to consult with their physician regarding alternate treatment options (see section 4.4 and 5.3).

Pregnancy

There is limited amount of data from the use of elafibranor in pregnant women.

Studies in pregnant animals have shown reproductive toxicity (see section 5.3).

Elafibranor is not recommended during pregnancy.

Lactation

It is unknown whether elafibranor or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. (see section 5.3).

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

In the pivotal phase 3 ELATIVE study, 161 participants were randomised in a 2:1 ratio to receive elafibranor 80 mg (n=108) or placebo (n=53) for at least 52 weeks. At the end of the double-blind (DB) period of the study, the median duration of exposure was 63.07 and 61.00 weeks in the elafibranor and placebo groups, respectively.

The most commonly reported adverse drug reactions associated with elafibranor in more than 10% of participants (n=108) were abdominal pain (11.1%), diarrhoea (11.1%), nausea (11.1%) and vomiting (11.1%). These were non-serious and mild to moderate in severity.

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).

System Organ Class

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1 000 to <1/100)

Nervous system disorders

Headache

Gastrointestinal disorders

Abdominal paina

Diarrhoea

Nausea

Vomiting

Constipation

Hepatobiliary disorders

Cholelithiasis

Skin and subcutaneous tissue disorders

Rash pruritic

Musculoskeletal and connective tissue disorders

Myalgia

Investigations

Blood CPK increased

Blood creatinine increased

a includes abdominal pain upper and abdominal pain lower

Description of selected adverse reactions

Nine (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).

Four (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 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.

Post-marketing experience

Not applicable

Paediatric population

Not applicable

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of suspected overdose, patients should be carefully observed, and appropriate symptomatic treatment and supportive care should be initiated.

Paediatric population

Not applicable