Elafibranor (Monograph)

Brand name: Iqirvo
Drug class: Cholelitholytic Agents

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

Introduction

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

Uses for Elafibranor

Elafibranor has the following uses:

Elafibranor 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 reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events has not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

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

Elafibranor Dosage and Administration

General

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

Tablets: 80 mg

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

Before treatment, evaluate for muscle pain or myopathy, and/or verify that females of reproductive potential are not pregnant.
The recommended dosage is 80 mg orally once daily with or without food.

Cautions for Elafibranor

Contraindications

None.

Warnings/Precautions

Myalgia, Myopathy, and Rhabdomyolysis

Rhabdomyolysis resulting in acute kidney injury occurred in one elafibranor-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with elafibranor alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor.

Assess for myalgia and myopathy prior to elafibranor initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with elafibranor, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt elafibranor treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis.

Fractures

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

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

Adverse Effects on Fetal and Newborn Development

Based on findings from animal reproduction studies, elafibranor may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body.

For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with elafibranor and for 3 weeks following the last dose of the drug.

Drug-induced Liver Injury

Drug-induced liver injury (DILI) occurred in one patient who took elafibranor 80 mg once daily and two patients who took elafibranor at 1.5-times the recommended dosage. In one patient who developed DILI while taking elafibranor at 1.5-times the recommended dosage, the clinical presentation was drug-induced autoimmune-like hepatitis (DI-ALH). The median time to onset of elevation in liver tests was 85 days (range: day 57 to 288). In the principal efficacy study, increases in transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≥ 5× ULN) occurred in 6% of elafibranor-treated patients compared to 6% of placebo-treated patients, and total bilirubin (TB) elevation (> 3× ULN) occurred in 2% of elafibranor-treated patients compared to no placebo-treated patients.

Obtain baseline clinical and laboratory assessments at treatment initiation with elafibranor and monitor thereafter according to routine patient management. Interrupt therapy if liver tests (ALT, AST, 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 the drug.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred in a clinical trial with elafibranor at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after elafibranor initiation, with positive dechallenges and rechallenges. Hypersensitivity reactions resolved after discontinuation of elafibranor and treatment with steroids and/or antihistamines.

If a severe hypersensitivity reaction occurs, permanently discontinue elafibranor. If a mild or moderate hypersensitivity reaction occurs, interrupt therapy and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after elafibranor rechallenge, then permanently discontinue the drug.

Biliary Obstruction

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

Specific Populations

Pregnancy

Based on data from animal reproduction studies, elafibranor may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose. There are insufficient data from human pregnancies exposed to elafibranor to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

The background risk of major birth defects and miscarriage for the indicated population is 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 2-4% and 15-20%, respectively.

Report pregnancies to Ipsen Pharmaceuticals, Inc. Adverse Event reporting line at 1-855-463-5127 and [[Web]

Lactation

There are no data available on the presence of elafibranor or its metabolites in human or animal milk, or on effects of the drug on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients not to breastfeed during treatment with elafibranor, and for 3 weeks after the last dose.

Females and Males of Reproductive Potential

Based on animal data, elafibranor may cause fetal harm when administered during pregnancy.

For females of reproductive potential, verify that the patient is not pregnant prior to initiating elafibranor.

Advise females of reproductive potential to use effective contraception (non-hormonal) or add a barrier method of contraception when using hormonal contraceptives during treatment with elafibranor and for 3 weeks after the last dose.

Pediatric Use

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

Geriatric Use

Of the 108 elafibranor-treated patients with primary biliary cholangitis, 25 (23%) were 65 years of age and older, while 1 (1%) was 75 years of age and older. No overall differences in effectiveness of elafibranor have been observed in patients 65 years of age and older compared to younger adult patients. In healthy elderly subjects (age range 75-80 years), mean systemic exposure (AUC) of elafibranor and the major active metabolite, GFT1007, was 23% and 52% higher, respectively, than those in healthy young subjects (age range 26 to 42 years).

No dosage adjustment for patients 65 years of age and older is necessary. However, because of limited clinical experience with elafibranor in patients older than 75 years old, closer monitoring of adverse events in patients older than 75 years is recommended.

Renal Impairment

The recommended dosage in patients with mild, moderate, or severe renal impairment is the same as in patients with normal kidney function.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

The safety and efficacy of elafibranor in patients with decompensated cirrhosis have not been established. Use of elafibranor 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 elafibranor if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).

Common Adverse Effects

Most common adverse reactions with elafibranor (reported in ≥ 5% and higher compared to placebo) are weight gain, diarrhea, abdominal pain, nausea, vomiting, arthralgia, constipation, muscle injury, fracture, gastroesophageal reflux disease, dry mouth, weight loss, and rash.

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:

Hormonal Contraceptives: Switch to effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives and for at least 3 weeks after last dose.
HMG-CoA Reductase Inhibitors: Monitor for signs and symptoms of muscle injury.
Rifampin: Monitor the biochemical response (e.g., alkaline phosphatase [ALP] and bilirubin) when patients initiate rifampin during elafibranor treatment.
Bile Acid Sequestrants: Administer at least 4 hours before or 4 hours after taking a bile acid binding sequestrant, or at as great an interval as possible.

Actions

Mechanism of Action

Elafibranor and its main active metabolite GFT1007 are peroxisome proliferator-activated receptor (PPAR) agonists, both of which activate PPAR-alpha, PPAR-gamma, and PPAR-delta in vitro. However, the mechanism by which elafibranor 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 PPAR-alpha and PPAR-delta. The signaling pathway for PPAR-delta was reported to include Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.

An in vitro PPAR functional assay showed that both elafibranor and GFT1007 produced activation of PPAR-alpha (EC₅₀ = 46 nM and 14 nM, respectively, and E_max = 56% and 61%, respectively, relative to reference agonists). The potency of elafibranor and GFT1007 for PPAR-alpha activation exceeded the respective potencies for PPAR-gamma and PPAR-delta activation by approximately 3- to 8-fold. Although the in vitro pharmacology studies detected PPAR-gamma activation by elafibranor and its metabolite GFT1007, toxicology studies in rats and monkeys (species with plasma metabolite profiles comparable to human) showed none of the adverse effects that are associated with PPAR-gamma activation.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients that elafibranor may cause rhabdomyolysis. Inform patients to report immediately to their healthcare provider any unexplained muscle symptoms such as pain, soreness, or weakness.
Inform patients or their caregiver(s) that elafibranor may increase the risk of bone fractures. Advise patients to call their healthcare provider to report any fractures.
Advise pregnant women and females of reproductive potential of the potential risk to the fetus and to inform their healthcare providers of a known, suspected, or planned pregnancy during treatment with elafibranor. Inform patients to report their pregnancy to Ipsen Biopharmaceuticals, Inc. at (1-855-463-5217). Advise females of reproductive potential to use effective contraception during treatment and for 3 weeks after the last dose.
Advise women not to breastfeed during treatment with elafibranor and for 3 weeks after the last dose.
Inform patients of the risk of elafibranor-induced liver injury. Instruct patients to report any signs or symptoms of liver injury (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider.
Inform patients of the risk of elafibranor-induced liver injury. Instruct patients to report any signs or symptoms of liver injury (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider.
Advise patients to contact their healthcare provider or go to the emergency department if hypersensitivity reactions, such as rash, occur.
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 elafibranor treatment can be interrupted while the patient is being evaluated.

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.