Livdelzi

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.

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.

<table width="90%"><caption>Table 1: Common Adverse Reactions Occurring Through Week 52 in Adult Patients with PBC (Trial 1)<footnote>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.</footnote></caption><col align="left" valign="top" width="40%"/><col align="center" valign="top" width="30%"/><col align="center" valign="top" width="30%"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction<footnote>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.</footnote></th><th styleCode="Rrule">LIVDELZI 10 mg Once Daily (N=128) % (n)</th><th styleCode="Rrule">PLACEBO (N=65) % (n)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">8% (10)</td><td styleCode="Rrule">3% (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnote ID="foot1">The gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI.</footnote></td><td styleCode="Rrule">7% (9)</td><td styleCode="Rrule">2% (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">6% (8)</td><td styleCode="Rrule">5% (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal distension<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">6% (8)</td><td styleCode="Rrule">3% (2)</td></tr><tr><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">5% (6)</td><td styleCode="Rrule">2% (1)</td></tr></tbody></table>