Livdelzi

1 INDICATIONS AND USAGE LIVDELZI 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 a reduction of alkaline phosphatase (ALP) [see Clinical Studies (14) ] . 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). LIVDELZI is a peroxisome proliferator-activated receptor (PPAR)-delta agonist 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). ( 1 ) Limitations of Use Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). ( 8.7 ) Limitations of Use Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy) [see Use in Specific Populations (8.7) ] .

2 DOSAGE AND ADMINISTRATION The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food. ( 2.1 ) 2.1 Recommended Dosage and Administration The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food [see Clinical Pharmacology (12.3) ] . 2.2 Administration Modification for Bile Acid Sequestrants Administer LIVDELZI at least 4 hours before or 4 hours after taking bile acid sequestrants, or at as great an interval as possible [see Drug Interactions (7.1) ] .

4 CONTRAINDICATIONS None. None.

5 WARNINGS AND PRECAUTIONS Fractures : Consider the risk of fracture in patients treated with LIVDELZI. Monitor bone health according to current standards of care. ( 5.1 ) Liver Test Abnormalities : Obtain baseline clinical and laboratory liver assessments prior to starting LIVDELZI and monitor during treatment. Interrupt or discontinue LIVDELZI if the liver tests worsen. ( 5.2 ) Biliary Obstruction : Avoid use in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated. ( 5.3 ) 5.1 Fractures Fractures occurred in 4% of LIVDELZI-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 LIVDELZI and monitor bone health according to current standards of care. 5.2 Liver Test Abnormalities LIVDELZI 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 LIVDELZI discontinuation. LIVDELZI 10 mg once daily did not show a similar pattern for increases in transaminase levels [see Overdosage (10) ] . Obtain baseline clinical and laboratory assessments at treatment initiation with LIVDELZI and monitor thereafter according to routine patient management. Interrupt LIVDELZI 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 LIVDELZI. 5.3 Biliary Obstruction Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated.

7 DRUG INTERACTIONS Probenecid : Avoid concomitant use. ( 7.1 ) Strong CYP2C9 Inhibitors : Monitor for adverse effects. ( 7.1 ) Dual Moderate CYP2C9 and Moderate to Strong CYP3A4 Inhibitors : Monitor for adverse effects. ( 7.1 ) CYP2C9 Poor Metabolizers using Moderate to Strong CYP3A4 Inhibitors : Monitor for adverse effects. ( 7.1 ) Dual or Multiple Clinical Inhibitors of Drug Transporters OATP1B1, OATP1B3, and BCRP : Monitor for adverse effects. ( 7.1 ) Rifampin : Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin. ( 7.1 ) 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. ( 7.1 ) 7.1 Effect of Other Drugs on LIVDELZI Table 2 includes clinically significant drug interactions affecting LIVDELZI. Table 2: Clinically Significant Interactions Affecting LIVDELZI Concomitant Drug or Class Potential Effect on Seladelpar Exposure ↑ = Increase, ↓ = Decrease. Clinical Intervention Probenecid ↑ seladelpar Avoid concomitant administration of LIVDELZI with probenecid. Strong CYP2C9 Inhibitors ↑ seladelpar Monitor patients for adverse effects during concomitant use of LIVDELZI with strong CYP2C9 inhibitors. Dual Moderate CYP2C9 and Moderate or Strong CYP3A4 Inhibitors (e.g., fluconazole) ↑ seladelpar Monitor patients for adverse effects during concomitant use of LIVDELZI with drugs that are dual moderate CYP2C9 and moderate or strong CYP3A4 inhibitors. CYP2C9 Poor Metabolizers Using Moderate or Strong CYP3A4 Inhibitors ↑ seladelpar Monitor patients who are CYP2C9 poor metabolizers for adverse effects during concomitant use of LIVDELZI with moderate or strong CYP3A4 inhibitor. Dual or Multiple Clinical Inhibitors of Drug Transporters OATP1B1, OATP1B3, and BCRP (e.g, cyclosporine) ↑ seladelpar Monitor patients for adverse effects during concomitant use of LIVDELZI with dual or multiple clinical inhibitors of drug transporters OATP1B1, OATP1B3, and BCRP. Rifampin ↓ seladelpar Concomitant use of LIVDELZI with rifampin, an inducer of metabolizing enzymes, may result in delayed or suboptimal LIVDELZI biochemical response. Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Bile Acid Sequestrants ↓ seladelpar Bile acid sequestrants may interfere with the action of LIVDELZI by reducing its absorption and systemic exposure, which may reduce LIVDELZI efficacy. Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible [see Dosage and Administration (2.2) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Fractures [see Warnings and Precautions (5.1) ] Liver Test Abnormalities [see Warnings and Precautions (5.2) ] Most common adverse reactions (reported in ≥5% and higher compared to placebo) are headache, abdominal pain, nausea, abdominal distension, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. In Trial 1, 193 patients were randomized to receive either LIVDELZI 10 mg (N=128) or placebo (N=65) once daily for 12 months [see Clinical Studies (14) ] . LIVDELZI or placebo was administered in combination with UDCA in 94% of patients and as monotherapy in 6% of patients who were unable to tolerate UDCA. Common Adverse Reactions Table 1 presents common adverse reactions that occurred in Trial 1. Table 1: Common Adverse Reactions Occurring Through Week 52 in Adult Patients with PBC (Trial 1) Included 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 patients (6%) in the LIVDELZI 10 mg arm and 4 patients (6%) in the placebo arm. Adverse Reaction Occurring in greater than or equal to 5% of patients in the LIVDELZI treatment arm and at an incidence greater than or equal to 1% higher than in the placebo arm. LIVDELZI 10 mg Once Daily (N=128) % (n) PLACEBO (N=65) % (n) Headache 8% (10) 3% (2) Abdominal pain The gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI. 7% (9) 2% (1) Nausea 6% (8) 5% (3) Abdominal distension 6% (8) 3% (2) Dizziness 5% (6) 2% (1) Fractures In Trial 1, fractures occurred in 4% (n=5) of LIVDELZI-treated patients compared to no placebo-treated patients. Baseline bone mineral density was not obtained. The median time to fracture after receiving LIVDELZI was 295 days (range: 89–349). Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the LIVDELZI-treated patients compared to placebo, but in less than 5% of patients, included dyspepsia, rash, alopecia, anemia, and cough. Laboratory Abnormalities Estimated Glomerular Filtration Rate In Trial 1, LIVDELZI-treated patients developed decreased estimated glomerular filtration rate (eGFR) (serum creatinine elevations) more frequently compared to placebo-treated patients. Ten percent (n=12) of LIVDELZI-treated patients had a decline in eGFR of at least 25%, compared to 2% (n=1) of placebo-treated patients. None of the patients experienced an eGFR decline of 50% or more. The decline in eGFR stabilized or returned towards baseline with ongoing LIVDELZI treatment. None of the patients required discontinuation of LIVDELZI and there were no clinical findings associated with the observed changes in eGFR.

8.1 Pregnancy Risk Summary There are insufficient data from human pregnancies exposed to LIVDELZI 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 (area under the plasma concentration-time curve), 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 was reduced at 115-times the recommended dose based on AUC, but not at the lower exposure of 16-times the recommended dose (see Data ) . 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. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day seladelpar (176-times the recommended dose based on AUC) during the period of organogenesis. Oral administration of 40 mg/kg/day seladelpar in pregnant rabbits (49-times the recommended dose based on AUC) during organogenesis resulted in reduced fetal body weight, which was likely due to maternal toxicity (i.e., decreases in food consumption, body weight, and gravid uterine weight) and distended stomach. No treatment-related fetal malformations or effects on embryo-fetal survival occurred in rabbits at 49-times the recommended dose. No adverse effects on embryo-fetal development were observed at 10 mg/kg/day (3-times the recommended dose based on AUC). A pre- and postnatal development study was performed using oral administration of seladelpar at doses of 0 (vehicle), 5, 20, or 100 mg/kg/day in pregnant rats during organogenesis through lactation. Treatment with 5 mg/kg/day or higher (4-times the recommended dose based on AUC) resulted in a dose-dependent reduction in pup body weight during the pre-weaning period. The weight reduction in offspring was associated with delays in developmental milestones (i.e., eye opening and pinna unfolding at 5 mg/kg/day and higher; hair growth and sexual maturity at 100 mg/kg/day). Reduction in pup body weight at 100 mg/kg/day (115-times the recommended dose based on AUC), which continued into the post-weaning maturation period, was associated with a slight decrease in pre-weaning survival and was considered adverse. No adverse effects were found in clinical observations, neurobehavioral assessment, or reproductive performance testing in the offspring of females treated with seladelpar. At 20 mg/kg/day (16-times the recommended dose based on AUC), none of the observed effects in offspring were considered to be adverse.