Seladelpar Lysine (Monograph)

Brand name: Livdelzi
Drug class: Cholelitholytic Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-delta agonist.

Uses for Seladelpar Lysine

Seladelpar has the following uses:

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

This indication is approved under accelerated approval based on a reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Use of seladelpar is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

Seladelpar Lysine Dosage and Administration

General

Seladelpar lysine is available in the following dosage form(s) and strength(s):

Capsules: 10 mg (of seladelpar)

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dosage of seladelpar is 10 mg orally once daily. Administer seladelpar with or without food.

Cautions for Seladelpar Lysine

Contraindications

None.

Warnings/Precautions

Fractures

Fractures occurred in 4% of seladelpar-treated patients compared to no placebo-treated patients.

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

Liver Test Abnormalities

Seladelpar has been associated with dose-related increases in serum transaminase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels greater than 3-times upper limit of normal (ULN) in PBC patients receiving 50 mg once daily (5-times higher than the recommended dosage) and 200 mg (20-times higher than the recommended dosage) once daily. Transaminase levels returned to pretreatment levels upon seladelpar discontinuation. Seladelpar 10 mg once daily did not show a similar pattern for increases in transaminase levels.

Obtain baseline clinical and laboratory assessments at treatment initiation with seladelpar and monitor thereafter according to routine patient management. Interrupt seladelpar treatment if the liver tests (ALT, AST, total bilirubin [TB], and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen 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.

Specific Populations

Pregnancy

There are insufficient data from human pregnancies exposed to seladelpar to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations or effects on embryo-fetal survival occurred in pregnant rats or rabbits after seladelpar treatment at exposures of up to 176-times and 49-times the recommended dose based on AUC, respectively. Reduction of fetal growth associated with maternal toxicity occurred in pregnant rabbits at 49-times the recommended dose based on AUC, but not at 3-times the recommended dose. In a pre- and postnatal development study in rats with maternal dosing of seladelpar during organogenesis through lactation, postnatal growth and pre-weaning survival of offspring were reduced at 115-times the recommended dose based on AUC, but not at the lower exposure of 16-times the recommended dose.

The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Report pregnancies to Gilead Sciences, Inc. at 1-800-445-3235.

Lactation

There are no data on the presence of seladelpar or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for seladelpar and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of seladelpar in pediatric patients have not been established.

Geriatric Use

Of the 128 seladelpar-treated patients in the principal efficacy study, 29 (23%) patients were 65 years of age and older and 2 (2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 to 75 years of age and younger adult patients. No dosage adjustment for patients 65 years of age and older is necessary.

Clinical studies of seladelpar did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger adult patients. Because of limited clinical experience with seladelpar in patients older than 75 years of age, closer monitoring of adverse events is recommended in such patients.

Renal Impairment

The recommended dosage in patients with mild, moderate, or severe renal impairment is the same as in patients with normal renal function. Patients with end-stage renal disease on dialysis have not been studied.

Hepatic Impairment

No dosage adjustment is recommended for patients with primary biliary cholangitis (PBC) who have mild hepatic impairment (Child-Pugh A).

The safety and efficacy of seladelpar in patients with decompensated cirrhosis have not been established. Use of seladelpar is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

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

CYP2C9 Poor Metabolizers

Monitor CYP2C9 poor metabolizers who receive a concomitant moderate to strong CYP3A4 inhibitor more frequently for adverse reactions.

Seladelpar is a CYP2C9 and CYP3A4 substrate. Increased seladelpar AUC is expected in patients who are CYP2C9 poor metabolizers with concomitant use of a moderate to strong CYP3A4 inhibitor.

Common Adverse Effects

Most common adverse reactions (reported in ≥5% and higher compared to placebo) are headache, abdominal pain, nausea, abdominal distension, and dizziness.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

OAT3 Inhibitors: Avoid concomitant use.
Strong CYP2C9 Inhibitors: Avoid concomitant use.
Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin.
Dual Moderate CYP2C9 and Moderate to Strong CYP3A4 Inhibitors: Monitor closely for adverse effects.
CYP2C9 Poor Metabolizers using Moderate to Strong CYP3A4 Inhibitors: Monitor more frequently for adverse effects.
BCRP Inhibitors: Monitor closely for adverse effects.
Bile Acid Sequestrants: Administer at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible.

Actions

Mechanism of Action

Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-delta (δ) agonist. However, the mechanism by which seladelpar exerts its therapeutic effects in patients with primary biliary cholangitis (PBC) is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPARδ, which is a nuclear receptor expressed in most tissues, including the liver. Published studies show that PPARδ activation by seladelpar reduces bile acid synthesis through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients that seladelpar may increase the risk of bone fractures. Advise patients to call their healthcare provider to report any fractures.
Instruct patients to report any signs or symptoms of liver-related adverse reactions (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider.
Instruct patients to immediately report any signs or symptoms of biliary obstruction (e.g., right upper quadrant pain, jaundice) to their healthcare provider so that seladelpar treatment can be interrupted while the patient is being evaluated.
Advise patients that there is a pregnancy safety study that captures pregnancy outcomes in women exposed to seladelpar during pregnancy, and to report pregnancies and pregnancy outcomes by calling 1-800-445-3235.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.