SELADELPAR GILEAD Hard capsule Ref.[115056] Active ingredients: Seladelpar

Liver test abnormalities

Dose dependent increases in serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) have been observed in patients receiving higher doses of seladelpar (see section 4.9). Obtain baseline clinical and laboratory assessments at initiation of treatment with seladelpar and monitor thereafter according to routine clinical practice. Consider temporary interruption of seladelpar treatment if liver tests worsen, or the patient develops signs and symptoms consistent with liver dysfunction. Consider permanent discontinuation if liver tests worsen again after restarting seladelpar.

Biliary Obstruction

Avoid use of seladelpar in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt seladelpar and treat as clinically indicated.

Co-administration of other medicinal products

Co-administration of probenecid with seladelpar is not recommended (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially ‘sodium-free’.

Effect of other medicinal products on seladelpar

Probenecid

Concomitant administration of seladelpar with probenecid (an OAT1, OAT3 and OATP1B1-inhibitor) is not recommended (see section 4.4). In a dedicated clinical drug interaction study, seladelpar area under the curve from zero to time infinity (AUC_0-inf) increased by 2-fold and maximum serum concentration (C_max) by 4.69-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid in healthy subjects.

Inhibitors of drug transporters

Concomitant administration of seladelpar with dual or multiple clinical inhibitors of drugs transporters including BCRP, OATP1B1, OATP1B3 and OAT3 (e.g cyclosporine) may result in an increase of seladelpar exposure. When seladelpar is concomitantly administered with dual or multiple clinical inhibitors of drugs transporters including BCRP, OATP1B1, OATP1B3, and OAT3, patients should be closely monitored for adverse effects.

In a dedicated clinical drug interaction study, seladelpar AUC_0-inf increased by 2.1-fold and C_max by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg cyclosporine (a BCRP, OATP1B1, OATP1B3 and CYP3A4 inhibitor) in healthy subjects.

CYP2C9 and CYP3A4 inhibitors

Seladelpar is primarily metabolized in vitro by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4. Concomitant administration of seladelpar with medicines that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate-to-strong CYP3A4 inhibitors may result in an increase in seladelpar exposure. When seladelpar is concomitantly administered with medicinal products that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate to strong CYP3A4 inhibitors (e.g. fluconazole, mifepristone), patients should be closely monitored for adverse effects.

In a dedicated clinical drug interaction study, seladelpar AUC_0-inf increased by 2.4-fold and C_max 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.

CYP2C9 inducers and strong CYP3A4 inducers

Concomitant administration of seladelpar with medicines that are CYP2C9 inducers and strong CYP3A4 inducers (e.g. rifampicin, a strong CYP3A4 and moderate CYP2C9 inducer) can decrease seladelpar exposure. When seladelpar is concomitantly administered with medicinal products that are CYP2C9 inducers and strong CYP3A4 inducers, patients should be monitored for a potential reduction in efficacy.

Seladelpar AUC_0-inf decreased by approximately 44% and C_max by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily in healthy subjects. The carbamazepine (a strong CYP3A and weak CYP2C9 inducer) dose was escalated from 100 mg to 300 mg over 7 days.

Bile acid binding resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam, may reduce the absorption of other medicinal products administered concurrently. Patients should take seladelpar at least 4 hours before or 4 hours after taking a bile acid binding resin.

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 at clinically relevant exposure levels (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of seladelpar during pregnancy.

Breast-feeding

It is unknown whether seladelpar or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from seladelpar therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of seladelpar on fertility are available.

Animal studies do not indicate any direct or indirect effects on fertility or the ability to reproduce.

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

Summary of safety profile

Based on clinical trial experience, the most frequently reported adverse reactions were abdominal pain (11.1%), headache (7.2%), nausea (6.5%) and abdominal distension (3.9%). These adverse reactions were non-serious and did not lead to discontinuation of seladelpar.

Tabulated list of adverse reactions

The frequencies of the adverse drug reactions provided in the table below are based on pooled data from the RESPONSE and ENHANCE trials unless otherwise stated.

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 clinical trials in patients treated with seladelpar:

^a Includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

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.