Elafibranor

Hormonal Contraceptives: Switch to progestin only products containing levonorgestrel/norgestrel, intrauterine systems, or effective non-hormonal contraceptives during treatment and for at least 3 weeks after last dose. ( 5.3 , 7.1 ) HMG-CoA Reductase Inhibitors : Monitor for signs and symptoms of muscle injury. ( 5.1 , 7.1 ) Strong CYP2C8 Inhibitors: Avoid concomitant use with strong CYP2C8 inhibitors (e.g. gemfibrozil). If concomitant use cannot be avoided, monitor patients for adverse reactions. ( 7.2 ) Other Peroxisome Proliferator-Activated Receptor-Alpha (PPAR-alpha) Agonists : Monitor for signs and symptoms of liver injury and muscle injury.

(7.2) Other PPAR-gamma Agonists : Monitor for signs and symptoms of liver injury (7.2) Rifampin: Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during IQIRVO treatment. ( 7.2 ) 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. ( 2.3 , 7.2 )

7.1 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 [see Clinical Pharmacology (12.3) ] . A clinical interaction study demonstrated that co-administration of IQIRVO and a combined oral hormonal contraceptive produced a decrease of ethinylestradiol which may lead to contraceptive failure and/or an increase in breakthrough bleeding, while levonorgestrel exposure remained unaffected.

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 [see Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ] . 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 [see Adverse Reactions (6.1) ] .

Intervention Monitor for signs and symptoms of muscle injury. Consider periodic assessment (clinical exam, CPK) during treatment. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain or myopathy [see Warnings and Precautions (5.1) ] .

7.2 Effects of Other Drugs on IQIRVO Table 4 includes clinically significant drug interactions affecting IQIRVO. 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 [see Clinical Pharmacology (12.3) ] , which may increase the risk of IQIRVO adverse reactions. Intervention Avoid concomitant use of IQIRVO with strong CYP2C8 inhibitors (e.g. gemfibrozil). If concomitant use cannot be avoided, monitor patients for adverse reactions.

Other Peroxisome Proliferator-Activated Receptor-Alpha (PPAR-alpha) Agonists Clinical impact Co-administration of IQIRVO with other PPAR-alpha agonists (e.g., fenofibrate, fenofibric acid) may increase risk of liver injury and muscle injury. Intervention Monitor for signs and symptoms of liver injury and muscle injury [see Warnings and Precautions (5.1 , 5.4) ] . 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 [see Warnings and Precautions (5.4) ].

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 [see Clinical Pharmacology (12.3) ] . Intervention Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during treatment with IQIRVO. Bile Acid Binding Sequestrants Clinical Impact Bile acid sequestrants may interfere with the action of IQIRVO by reducing its absorption and systemic exposure, which may reduce IQIRVO efficacy.

Intervention 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 [see Dosage and Administration (2.3) ] .

8.1 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 [area under the plasma concentration-time curve] 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…