IQIRVO

5 WARNINGS AND PRECAUTIONS Myalgia, Myopathy, and Rhabdomyolysis : Assess for muscle pain and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement). Interrupt IQIRVO if there is new onset or worsening of muscle injury, or muscle pain. ( 5.1 ) Fractures: The risk of fracture should be considered in the care of patients treated with IQIRVO. Apply current standards of care for assessing and maintaining bone health. ( 5.2 ) Adverse Effects on Fetal and Newborn Development : May cause fetal harm. Verify that a female of reproductive potential is not pregnant prior to initiating IQIRVO. Advise females of reproductive potential to avoid use of hormonal contraceptives containing ethinyl estradiol and to use alternative contraception. ( 5.3 , 8.1 , 8.3 ) Drug-Induced Liver Injury : Obtain clinical and laboratory assessments at treatment initiation and monitor thereafter according to routine patient management. Interrupt the treatment if liver tests worsen, or patients develop signs and symptoms consistent with clinical hepatitis. Consider permanent discontinuation if liver tests worsen after restarting IQIRVO. ( 5.4 ) Hypersensitivity Reactions : If severe hypersensitivity reactions occur, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor until signs and symptoms resolve. ( 5.5 ) Biliary Obstruction : Avoid use in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated. ( 5.6 ) 5.1 Myalgia, Myopathy, and Rhabdomyolysis Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-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 IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor [see Adverse Reactions (6.1) ] . Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis. IQIRVO may be restarted if an alternative etiology for these signs and symptoms has been identified and resolved. However, discontinue IQIRVO if signs and symptoms recur. Patients concomitantly taking peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists (e.g., fenofibrate, fenofibric acid) may have an increased risk of muscle injury. Monitor for signs and symptoms of muscle injury during concomitant use with IQIRVO [see Drug Interactions (7.2) ] . 5.2 Fractures Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients [see Adverse Reactions (6.1) ] . Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care. 5.3 Adverse Effects on Fetal and Newborn Development Based on findings from animal reproduction studies, IQIRVO 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 [see Use in Specific Populations (8.1) ] . For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. IQIRVO may reduce the effectiveness of hormonal contraceptives containing ethinyl estradiol. Advise females of reproductive potential to avoid use of hormonal contraceptives containing ethinyl estradiol and to use alternative contraception, including progestin-only contraceptives containing levonorgestrel/norgestrel, intrauterine systems, or effective non-hormonal contraceptives during treatment with IQIRVO and for 3 weeks after the last dose of IQIRVO [see Drug Interactions (7.1) , Use in Specific Populations (8.3) ]. 5.4 Drug-Induced Liver Injury Drug-induced liver injury (DILI) occurred in one patient who took IQIRVO 80 mg once daily [see Adverse Reactions (6.1) ] and two patients who took IQIRVO at 1.5-times the recommended dosage. In one patient who developed DILI while taking IQIRVO 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 Study 1, increases in transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≥ 5× ULN) occurred in 6% of IQIRVO-treated patients compared to 6% of placebo-treated patients, and total bilirubin (TB) elevation (> 3× ULN) occurred in 2% of IQIRVO-treated patients compared to no placebo-treated patients . Obtain baseline clinical and laboratory assessments at treatment initiation with IQIRVO and monitor thereafter according to routine patient management. Interrupt IQIRVO treatment 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 IQIRVO. Patients concomitantly taking PPAR-alpha agonists (e.g., fenofibrate, fenofibric acid) and/or PPAR-gamma agonists (e.g., pioglitazone, rosiglitazone) may have an increased risk of liver injury. Monitor for signs and symptoms of liver injury during concomitant use with IQIRVO [see Drug Interactions (7.2) ]. 5.5 Hypersensitivity Reactions Hypersensitivity reactions have occurred in a clinical trial with IQIRVO at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after IQIRVO initiation, with positive dechallenges and rechallenges. Hypersensitivity reactions resolved after discontinuation of IQIRVO and treatment with steroids and/or antihistamines. If a severe hypersensitivity reaction occurs, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO. 5.6 Biliary Obstruction Avoid use of IQIRVO in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated [see Adverse Reactions (6.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myalgia, Myopathy, and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Fractures [see Warnings and Precautions (5.2) ] Drug-Induced Liver Injury [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions with IQIRVO (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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The safety of IQIRVO is based on Study 1 consisting of 161 patients who were randomized to receive IQIRVO 80 mg (n=108) or placebo (n=53) once daily with a median duration of exposure during the double-blind period of 62 weeks (inter quartile range: 52, 84) [see Clinical Studies (14) ] . 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. Table 1: Common Adverse Reactions Occurring During the Double-Blind Period in Adult Patients with PBC (Study 1) Included 8 patients (5%) who were intolerant to UDCA and initiated treatment as monotherapy: 6 patients (5%) in the IQIRVO arm and 2 patients (4%) in the placebo arm. Adverse Reaction Occurring in greater than or equal to 5% of patients in the IQIRVO treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm. IQIRVO 80 mg Once Daily N = 108 % (n) Placebo N = 53 % (n) Weight gain Weight gain, abdominal pain, muscle pain, fracture, and rash include other related terms. 23% (25) 21% (11) Diarrhea 11% (12) 9% (5) Abdominal pain 11% (12) 6% (3) Nausea 11% (12) 6% (3) Vomiting 11% (12) 2% (1) Arthralgia 8% (9) 4% (2) Constipation 8% (9) 2% (1) Muscle pain 7% (8) 2% (1) Fracture 6% (7) 0 Gastroesophageal reflux disease 6% (7) 2% (1) Dry mouth 5% (5) 2% (1) Weight loss 5% (5) 0 Rash 5% (5) 4% (2) Gastrointestinal Adverse reactions Gastrointestinal symptoms were observed in 35 (32%) IQIRVO-treated patients compared to 6 (11%) in the placebo-treated patients. The severity of gastrointestinal events was mild in 43% of events and was moderate in 51% of events. The median time to onset was 13 (0.3 to 92) weeks for diarrhea, 4 (0.1 to 26) weeks for nausea, and 23 (4 to 55) weeks for vomiting. The median duration of events was 0.6 (0.3 to 86) weeks for diarrhea, 2 (0.1 to 89) weeks for nausea and 0.3 (0.1 to 51) weeks for vomiting without requiring discontinuation of IQIRVO. 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. Table 2: Muscle Injury Related Adverse Reactions During the Double-Blind Period in Adult Patients with PBC in Study 1 Adverse Reaction IQIRVO 80 mg Once Daily N = 108 % (n) Placebo N = 53 % (n) Creatine phosphokinase (CPK) increased (>3× ULN) 4% (4) Two patients receiving IQIRVO 80 mg once daily were on a concomitant HMG-CoA reductase inhibitor 0 Myalgia 4% (4) 2% (1) CPK increased and Myalgia 1% (1) One patient receiving IQIRVO 80 mg once daily was on a concomitant HMG-CoA reductase inhibitor 0 Rhabdomyolysis and AKI AKI: Acute kidney injury 1% (1) 0 Fractures Fractures occurred in 6% (n=7) of IQIRVO-treated patients compared to no placebo-treated patients. 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.

<table width="75%"><caption>Table 1: Common Adverse Reactions Occurring During the Double-Blind Period in Adult Patients with PBC (Study 1)<footnote>Included 8 patients (5%) who were intolerant to UDCA and initiated treatment as monotherapy: 6 patients (5%) in the IQIRVO arm and 2 patients (4%) in the placebo arm.</footnote></caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction<footnote>Occurring in greater than or equal to 5% of patients in the IQIRVO treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm.</footnote></th><th styleCode="Rrule">IQIRVO 80 mg Once Daily N = 108 % (n)</th><th styleCode="Rrule">Placebo N = 53 % (n)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight gain<footnote ID="ft1">Weight gain, abdominal pain, muscle pain, fracture, and rash include other related terms.</footnote></td><td styleCode="Rrule">23% (25)</td><td styleCode="Rrule">21% (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">11% (12)</td><td styleCode="Rrule">9% (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">11% (12)</td><td styleCode="Rrule">6% (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">11% (12)</td><td styleCode="Rrule">6% (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">11% (12)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">8% (9)</td><td styleCode="Rrule">4% (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">8% (9)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Muscle pain<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">7% (8)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fracture<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">6% (7)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastroesophageal reflux disease</td><td styleCode="Rrule">6% (7)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry mouth</td><td styleCode="Rrule">5% (5)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight loss</td><td styleCode="Rrule">5% (5)</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Rash<footnoteRef IDREF="ft1"/></td><td styleCode="Rrule">5% (5)</td><td styleCode="Rrule">4% (2)</td></tr></tbody></table>

<table width="85%"><caption>Table 2: Muscle Injury Related Adverse Reactions During the Double-Blind Period in Adult Patients with PBC in Study 1</caption><col width="60%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center">Adverse Reaction</th><th styleCode="Rrule">IQIRVO 80 mg Once Daily N = 108 % (n)</th><th styleCode="Rrule">Placebo N = 53 % (n)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatine phosphokinase (CPK) increased (&gt;3&#xD7; ULN)</td><td styleCode="Rrule">4% (4)<footnote ID="ft2">Two patients receiving IQIRVO 80 mg once daily were on a concomitant HMG-CoA reductase inhibitor</footnote></td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">4% (4)<footnoteRef IDREF="ft2"/></td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">CPK increased and Myalgia</td><td styleCode="Rrule">1% (1)<footnote ID="ft3">One patient receiving IQIRVO 80 mg once daily was on a concomitant HMG-CoA reductase inhibitor</footnote></td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Rhabdomyolysis and AKI<footnote>AKI: Acute kidney injury</footnote></td><td styleCode="Rrule">1% (1)<footnoteRef IDREF="ft3"/></td><td styleCode="Rrule">0</td></tr></tbody></table>