4.1. Therapeutic indications

LIVDELZI® is indicated for the treatment of primary biliary cholangitis (PBC), including pruritus, in adults in combination with ursodeoxycholic acid (UDCA) who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA.

4.2. Posology and method of administration

The recommended dosage of LIVDELZI is 10 mg once daily.

Posology

Prior to initiation of treatment with LIVDELZI the patient's hepatic status must be known. Whether the patient has decompensated cirrhosis (including Child-Pugh Class B and C) or has had a prior decompensation event should be determined prior to initiation of treatment.

Special Populations

Paediatric population

There is no relevant use of LIVDELZI in the paediatric population in the treatment of PBC.

Elderly

Limited data exists in elderly patients aged 75 years or older. No dose adjustment is required for elderly patients (see sections 5.2). No data are available in subjects aged 80 years of age or older.

Renal impairment

No dose adjustment of LIVDELZI is required for patients with mild, moderate and severe renal impairment. Patients with end-stage renal disease on dialysis have not been studied (see section 5.2).

Hepatic impairment

No dose adjustment is required in PBC patients with mild hepatic impairment (Child-Pugh A).

Safety and efficacy of LIVDELZI in patients with decompensated cirrhosis have not been established. Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (see section 5.2).

Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuing LIVDELZI if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).

Method of administration

LIVDELZI can be taken with or without food.

For patients taking a bile acid binding resin, LIVDELZI should be taken at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as long an interval as possible (see section 4.5).

4.3. Contraindications

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

- Patients with complete biliary obstruction

4.4. Special warnings and precautions for use

Transaminase Elevations

LIVDELZI has been associated with dose related increases in serum transaminase (AST and ALT) levels greater than 3 times upper limit of normal (ULN) in patients with PBC receiving doses of 50 and 200 mg/day (5- and 20-times the recommended 10 mg/day dose). Transaminase levels returned to pretreatment levels upon treatment discontinuation. No pattern for increases in transaminases levels was observed at lower doses (2, 5 or 10 mg).

Obtain baseline clinical and laboratory assessments at initiation of treatment with LIVDELZI and monitor thereafter according to routine clinical practice. Interrupt LIVDELZI treatment if the liver tests (ALT, AST, total bilirubin, and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis. Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI.

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

Bile Acid Binding Resins

Bile acid binding resins may reduce the absorption of other drugs administered concurrently. Patients should take LIVDELZI at least 4 hours before or 4 hours after taking a bile acid binding resin.

CYP2C9 and CYP3A4 Inhibitors

Concomitant administration of seladelpar with medicines that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate-to-strong CYP3A inhibitors (e.g. fluconazole, mifepristone), may result in an increase in seladelpar exposure. When seladelpar is concomitantly administered with drugs that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate to strong CYP3A4 inhibitors, patients should be closely monitored for adverse effects.

Ciclosporin

Concomitant administration of seladelpar with ciclosporin may result in an increase in seladelpar exposure. When seladelpar is concomitantly administered with ciclosporin, patients should be closely monitored for adverse effects.

Probenecid

Concomitant administration of seladelpar with probenecid may result in an increase in seladelpar exposure. Avoid concomitant administration of seladelpar with probenecid.

Drug Interaction Studies

In vitro Assessment of Drug Interactions

Based on in vitro studies, seladelpar and its metabolites (M1, M2, or M3) are not expected to inhibit CYPs 1A2, 2B6, 2C8, 2C19, 2D6, or UGTs at the recommended dose of 10 mg.

Seladelpar did not induce CYP1A2, CYP2B6, or CYP2C8. Seladelpar and its metabolites (M1, M2, or M3) are not expected to inhibit drug transporters including P-gp, MATE1, MATE2-K, OCT1, OAT1, and OAT3 at the recommended dose of 10 mg.

Seladelpar is a substrate of BCRP, P-gp, and OAT3 transporters in vitro. Seladelpar is not a substrate of MATE1, MATE2-K, OAT1, OCT1, or OCT2.

Effect of Seladelpar on Other Drugs

Seladelpar has no clinically relevant effect on the pharmacokinetics of tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), and rosuvastatin (OATP and BCRP substrate).

Effect of Other Drugs on Seladelpar

Fluconazole

Seladelpar AUC0-inf increased by 2.4-fold and Cmax by 1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects.

Carbamazepine

Seladelpar AUC0-inf decreased by approximately 44% and Cmax by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily in healthy subjects.

Quinidine

Seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (P-gp inhibitor) was co-administered in healthy subjects.

Ciclosporin

Seladelpar AUC0-inf increased by 2.1-fold and Cmax by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg ciclosporin (OATP1B1, OATP1B3, P-gp, BCRP, MRP2, and CYP3A inhibitor) in healthy subjects.

Probenecid

Seladelpar AUC0-inf increased by 2-fold and Cmax by 4.7-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid (OAT1, OAT3, OATP1B1, and UGT inhibitor) in healthy subjects.

Other drugs

No clinically significant differences in seladelpar pharmacokinetics were predicted with concomitant use of strong CYP3A4 inhibitors or CYP2C8 inhibitors.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of seladelpar in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of LIVDELZI during pregnancy.

Breast-feeding

It is unknown whether seladelpar/metabolites are excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI or from the underlying maternal condition.

Fertility

No fertility data are available in humans. Seladelpar did not affect fertility in male or female rats at oral doses up to 100 mg/kg/day (see section 5.3).

4.7. Effects on ability to drive and use machines

LIVDELZI has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of Safety Profile

Based on clinical trial experience, the most frequently reported adverse reactions were headache, nausea, abdominal pain and abdominal distension which occurred in more than 5% of patients.

Tabulated list of adverse reactions

The frequencies of the adverse drug reactions observed in the pivotal RESPONSE study are provided in the table below.

Adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT).

Frequencies are defined according to the following convention: 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 drug reactions reported in PBC patients treated with LIVDELZI

System Organ Class

Common

Nervous System Disorders

Headache

Gastrointestinal Disorders

Nausea, abdominal pain, abdominal distension

Safety profile from open label study

In ASSURE, an open label safety study, LIVDELZI was evaluated in 280 PBC patients, of whom 206 were treated with LIVDELZI for at least 6 months, 144 were treated for at least 12 months, and 19 were treated for at least 2 years. In this study the safety profile was similar to that in the pivotal study (RESPONSE).

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

4.9. Overdose

There is no specific treatment for overdose with LIVDELZI. General supportive care of the patient is indicated, as appropriate. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because LIVDELZI is highly bound to plasma proteins, haemodialysis should not be considered.