Iqirvo Drug Information

IQIRVO is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had 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 have not been demonstrated.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

Recommended Evaluation Before Initiating IQIRVO

Before initiating IQIRVO: Evaluate for muscle pain or myopathy. Verify that females of reproductive potential are not pregnant prior to initiating treatment with IQIRVO.

Recommended Dosage and Administration

The recommended dosage of IQIRVO is 80 mg taken orally once daily with or without food.

Administration Modification for Bile Acid Sequestrants Administer IQIRVO at least 4 hours before or 4 hours after administering the bile acid sequestrant, or at as great an interval as possible.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. IQIRVO or placebo was administered in combination with UDCA in 95% of patients and as monotherapy in 5% of patients who were unable to tolerate UDCA. The most common adverse reaction leading to treatment discontinuation was increased CPK (4%).

Common Adverse Reactions Table 1 presents common adverse reactions that occurred in Study 1. The severity of gastrointestinal events was mild in 43% of events and was moderate in 51% of events. Myalgia, Myopathy, and Rhabdomyolysis Muscle injury included rhabdomyolysis, CPK elevation with or without myalgia, and myopathy.

Rhabdomyolysis and acute kidney injury (AKI) occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also on a stable dose of an HMG-CoA reductase inhibitor for a year. Median time to development of myalgia was 85.5 days (interquartile range: 29, 291). CPK elevation and/or myalgia occurred in patients on IQIRVO monotherapy as well as in patients who were concomitantly treated with an HMG-CoA reductase inhibitor.

Table 2 presents the frequency of muscle injury related adverse reactions in Study 1. The median time to fracture after receiving IQIRVO was 122 days (interquartile range: 48, 258). Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the IQIRVO-treated patients compared to placebo, but in less 5% of patients included dizziness, gastroenteritis, increased blood creatinine, and anemia.

Cholelithiasis and Cholecystitis New onset of cholelithiasis was detected in 3 (3%) IQIRVO-treated patients compared to no placebo-treated patients. The three IQIRVO-treated patients were taking UDCA concomitantly. An additional patient who had gallstones at baseline developed cholecystitis requiring cholecystectomy.

Effects of IQIRVO on Other Drugs Table 3 includes clinically significant drug interactions affecting other drugs. Table 3: Clinically Significant Interactions Affecting Other Drugs Hormonal Contraceptives Clinical Impact IQIRVO is a weak CYP3A4 inducer. Intervention Switch to progestin only product containing levonorgestrel/norgestrel, intrauterine system, or effective non-hormonal contraceptives when using hormonal contraceptives during treatment with IQIRVO and for at least 3 weeks after last dose.

HMG-CoA Reductase Inhibitors Clinical Impact CPK elevation and/or myalgia occurred in patients on IQIRVO monotherapy. Co-administration of IQIRVO and HMG-CoA reductase inhibitors (statins) which have a risk of myalgia, can increase the risk of myopathy by a mechanism that has not been fully characterized. Intervention Monitor for signs and symptoms of muscle injury.

Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain or myopathy.

Table 4: Clinically Significant Interactions Affecting IQIRVO Strong CYP2C8 Inhibitors Clinical Impact The major active metabolite of elafibranor, GFT1007, is a CYP2C8 substrate. Concomitant use with a strong CYP2C8 inhibitor may increase systemic exposure of GFT1007, which may increase the risk of IQIRVO adverse reactions. Monitor for signs and symptoms of liver injury and muscle injury.

Other Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) Agonists Clinical impact Co-administration of IQIRVO with PPAR-gamma agonists (e.g., pioglitazone, rosiglitazone) may increase risk of liver injury. Intervention Monitor for signs and symptoms of liver injury. Rifampin Clinical Impact Co-administration of IQIRVO with rifampin, an inducer of metabolizing enzymes, may reduce the systemic exposure of elafibranor and its active metabolite via increased metabolism and may result in delayed or suboptimal biochemical response.

Administer IQIRVO at least 4 hours before or 4 hours after taking a bile acid binding sequestrant, or at as great an interval as possible.

Pregnancy Risk Summary Based on data from animal reproduction studies, IQIRVO 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 ( see Data ). There are insufficient data from human pregnancies exposed to IQIRVO 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.

There is a pregnancy safety study for IQIRVO. If IQIRVO is administered during pregnancy, healthcare providers should report IQIRVO exposure by contacting Ipsen Biopharmaceuticals, Inc. at 1-844-990-0239 or www.iqirvopregnancyregistry.com. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 300 mg/kg/day elafibranor (15-times the recommended dose based on combined AUC for elafibranor and GFT1007) during the period of organogenesis.

No adverse effects on embryo-fetal development were observed in pregnant rabbits treated orally with doses up to 100 mg/kg/day elafibranor, which produced systemic exposures (combined AUC for elafibranor and GFT1007) during the period of organogenesis that were less than the human exposure. Administration of 300 mg/kg/day (3.9-times the recommended dose based on combined AUC for elafibranor and GFT1007) produced marked maternal toxicity, embryo-lethality, reduced fetal weight, and a low incidence of fetal malformations. Variations in ossification of distal limb bones occurred at 100 mg/kg/day, which was associated with strong signs of maternal toxicity (e.g., body weight loss).

A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation. All doses produced a reduction in pup survival (during postnatal days 1-4 at 100 mg/kg/day and postnatal days 5-21 at 10 mg/kg/day and higher), a decrease in pup body weight (dose-dependent, up to -28% on postnatal day 1), blue/black discoloration of the caudal section of body, and developmental delays based on evaluation of physical landmarks and functional tests. The developmental delays were likely caused by the decrease in body weight.

Adverse effects in the offspring occurred at maternal exposures at or above 0.6-times the recommended dose based on combined AUC for elafibranor and GFT1007. Stillbirths were observed in the 30 and 100 mg/kg/day groups (1.3 and 4.9-times the recommended dose, respectively, based on combined AUC for elafibranor and GFT1007). Aortic or iliac arterial thrombosis was found in decedent pups from females treated with 30 or 100 mg/kg/day.

The surviving adult offspring showed no effects on learning and memory, reflex development, or reproductive capability.

Pediatric Use The safety and effectiveness of IQIRVO have not been established in pediatric patients.