Lynavoy

5 WARNINGS AND PRECAUTIONS Liver Test Elevations: Obtain baseline liver tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin [TB], direct bilirubin [DB], alkaline phosphatase [ALP]) and monitor the levels per standard clinical practice during treatment. If new liver test elevations occur, monitor ALT, AST, TB, DB, and ALP more frequently. For persistent liver test elevations, discontinue LYNAVOY. ( 5.1 ) Diarrhea: Diarrhea may occur. Advise patient to monitor for dehydration. Treatment interruption or discontinuation may be required if diarrhea persists. ( 5.2 ) Fat-Soluble Vitamin (FSV) Deficiency: Obtain baseline levels and monitor during treatment. Supplement with FSV if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, consider permanent discontinuation of treatment. ( 5.3 ) Bleeding: Interrupt treatment with LYNAVOY if bleeding occurs. Optimize treatment of FSV deficiency and consider restarting LYNAVOY once the patient is clinically stable. Fracture: IBAT inhibitors have been associated with bone fractures. Monitor bone health and ensure adequate FSV levels. 5.1 Liver Test Elevations In Study 1, liver test elevations were observed more commonly in LYNAVOY-treated patients compared to placebo-treated patients [see Adverse Reactions (6.1) ] . Obtain baseline liver tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin [TB], direct bilirubin [DB], alkaline phosphatase [ALP]) prior to initiating treatment with LYNAVOY and monitor the levels per standard clinical practice for PBC patients during treatment with LYNAVOY. If new liver test elevations occur, monitor ALT, AST, TB, DB, and ALP more frequently. If liver test elevations persist, discontinue LYNAVOY. 5.2 Diarrhea Diarrhea was reported as the most common adverse reaction in patients treated with LYNAVOY [see Adverse Reactions (6.1) ] . If diarrhea occurs, advise patients to monitor for dehydration. Consider interrupting or discontinuing LYNAVOY treatment if diarrhea persists. 5.3 Fat-Soluble Vitamin Deficiency LYNAVOY may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K [see Adverse Reactions (6.1) ]. Obtain serum FSV levels (vitamins A, D, and E) and INR prior to initiation of LYNAVOY and monitor the levels periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if FSV deficiency is diagnosed. Consider discontinuing LYNAVOY if FSV deficiency persists or worsens despite adequate FSV supplementation. Bleeding Bleeding was observed more frequently in LYNAVOY-treated patients compared to placebo-treated patients [see Adverse Reactions (6.1) ] . If bleeding occurs, interrupt LYNAVOY treatment and evaluate for potential FSV deficiency. LYNAVOY can be restarted if FSV deficiency is corrected, levels are maintained, and bleeding has resolved. Bone Fracture IBAT inhibitors have been associated with bone fractures. Monitor bone health and ensure adequate FSV levels.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Liver Test Elevations [see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precautions (5.2) ] Fat-Soluble Vitamin Deficiency [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥5%) are: diarrhea, abdominal pain, nausea, increased ALT, hemorrhage, increased AST, headache, dyspepsia, gastroesophageal reflux disease, abdominal distension, dizziness, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals 1-844-782-4278 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of LYNAVOY is based on Study 1, a randomized, double-blind, placebo-controlled, 24-week study of LYNAVOY 40 mg administered orally twice daily [see Clinical Studies (14) ] . Drug discontinuation due to adverse reactions was seen more frequently in LYNAVOY-treated patients (14%) than in placebo-treated patients (5%). Diarrhea, abdominal pain, ALT increase, and AST increase were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays the most common adverse reactions that occurred in at least 5% of LYNAVOY-treated patients in Study 1. Table 1. Adverse Reactions Occurring in ≥5% of Adult Patients with PBC Treated with LYNAVOY in Study 1 (24 weeks), Safety Dataset Adverse reactions were only included in table above if they occurred more frequently in patients treated with LYNAVOY compared to placebo-treated patients. Adverse Reaction LYNAVOY (n = 119) n (%) Placebo (n = 118) n (%) Diarrhea Diarrhea includes diarrhea and frequent bowel movements. 74 (62) 21 (18) Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort. 31 (26) 12 (10) Nausea 12 (10) 11 (9) Increased alanine aminotransferase (ALT) 11 (9) 4 (3) Hemorrhage Hemorrhage includes contusion, ecchymosis, epistaxis, gastric hemorrhage, hematochezia, hemorrhagic disorder, intermenstrual bleeding, melena, petechiae, skin hemorrhage, vaginal hemorrhage, hematocrit decreased, and diarrhea hemorrhagic. 11 (9) 3 (3) Increased aspartate aminotransferase (AST) 10 (8) 1 (<1) Headache 10 (8) 4 (3) Dyspepsia 9 (8) 1 (<1) Gastroesophageal reflux disease 8 (7) 5 (4) Abdominal distension 8 (7) 6 (5) Dizziness 7 (6) 4 (3) Arthralgia 7 (6) 6 (5) Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the LYNAVOY group compared to placebo group, in less than <5% of patients, included hyperbilirubinemia, hypertriglyceridemia, urinary tract infections, and dry mouth. Specific Adverse Reactions Liver Test Elevations In Study 1, liver test elevations (ALT, AST, TB, or ALP) were observed more commonly in LYNAVOY-treated patients 17 (14%) compared to placebo-treated patients 7 (6%). Six (5%) of LYNAVOY-treated patients discontinued treatment due to liver test elevations during the study, compared to 2 (2%) of placebo-treated patients. Elevations in ALT to more than 3 times baseline levels occurred in 8 (7%) of LYNAVOY-treated patients compared to 4 (3%) of placebo-treated patients. Elevations in TB to more than 2 times baseline levels occurred in 9 (8%) of LYNAVOY-treated patients compared to 3 (3%) of placebo-treated patients. Diarrhea In Study 1, diarrhea was observed in 74 (62%) of patients in the LYNAVOY-treated group compared to 21 (18%) in the placebo-treated group. Most diarrhea events occurred within the first 20 days of initiating treatment. Of those who experienced diarrhea, 56/74 (76%) of LYNAVOY-treated patients and 10/21 (48%) of placebo-treated patients, did so within the first 20 days. Of the patients who experienced diarrhea, most were mild (46/74, 62%) or moderate (25/74, 34%) with 4% (3/74) of cases being severe in the LYNAVOY-treated group compared to 62% (13/21) mild, 38% (8/21) moderate, and 0% severe cases in the placebo-treated group. Discontinuation of treatment due to diarrhea occurred in 4% of patients in the LYNAVOY-treated group compared to <1% in the placebo group. Fat-Soluble Vitamin Deficiency In Study 1, FSV deficiency was reported in 2 (2%) of LYNAVOY-treated patients compared to 1 (<1%) of placebo-treated patients during the 24 weeks of treatment.

<table width="90%"><caption>Table 1. Adverse Reactions Occurring in &#x2265;5% of Adult Patients with PBC Treated with LYNAVOY in Study 1 (24 weeks), Safety Dataset<footnote>Adverse reactions were only included in table above if they occurred more frequently in patients treated with LYNAVOY compared to placebo-treated patients.</footnote></caption><col width="46%" align="left" valign="bottom"/><col width="27%" align="center" valign="bottom"/><col width="27%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">LYNAVOY (n = 119) n (%)</th><th styleCode="Rrule">Placebo (n = 118) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea<footnote>Diarrhea includes diarrhea and frequent bowel movements.</footnote></td><td styleCode="Rrule">74 (62)</td><td styleCode="Rrule">21 (18)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnote>Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort. </footnote></td><td styleCode="Rrule">31 (26)</td><td styleCode="Rrule">12 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">12 (10)</td><td styleCode="Rrule">11 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased alanine aminotransferase (ALT)</td><td styleCode="Rrule">11 (9)</td><td styleCode="Rrule">4 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemorrhage<footnote>Hemorrhage includes contusion, ecchymosis, epistaxis, gastric hemorrhage, hematochezia, hemorrhagic disorder, intermenstrual bleeding, melena, petechiae, skin hemorrhage, vaginal hemorrhage, hematocrit decreased, and diarrhea hemorrhagic.</footnote></td><td styleCode="Rrule">11 (9)</td><td styleCode="Rrule">3 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased aspartate aminotransferase (AST)</td><td styleCode="Rrule">10 (8)</td><td styleCode="Rrule">1 (&lt;1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">10 (8)</td><td styleCode="Rrule">4 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">9 (8)</td><td styleCode="Rrule">1 (&lt;1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastroesophageal reflux disease</td><td styleCode="Rrule">8 (7)</td><td styleCode="Rrule">5 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal distension</td><td styleCode="Rrule">8 (7)</td><td styleCode="Rrule">6 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">7 (6)</td><td styleCode="Rrule">4 (3)</td></tr><tr><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">7 (6)</td><td styleCode="Rrule">6 (5)</td></tr></tbody></table>