Linerixibat

LYNAVOY is indicated for the treatment of cholestatic pruritus associated with primary biliary cholangitis (PBC) in adult patients. Limitations of Use Avoid use of LYNAVOY in patients with decompensated cirrhosis or those with prior or active hepatic decompensation events (e.g. variceal hemorrhage, ascites, hepatic encephalopathy) [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . LYNAVOY is an ileal bile acid transporter (IBAT) inhibitor indicated for the treatment of cholestatic pruritus associated with primary biliary cholangitis (PBC) in adult patients. ( 1 ) Limitations of Use Avoid use of LYNAVOY in patients with decompensated cirrhosis or those with prior or active hepatic decompensation events (e.g. variceal hemorrhage, ascites, hepatic encephalopathy). ( 1 )

The recommended dosage of LYNAVOY is 40 mg taken orally twice daily. Swallow tablets whole at least 30 minutes before any food or beverage (other than water). ( 2.1 )

2.1 Recommended Dosage The recommended dosage of LYNAVOY is 40 mg orally twice daily. Swallow tablets whole at least 30 minutes before any food or beverage (other than water) [see Clinical Pharmacology (12.3) ] . If a dose is missed, take the missed dose as soon as possible and at least 30 minutes before your next meal, then resume the original dosing schedule. If a dose is missed by more than 6 hours, skip the dose and resume the original dosing schedule. Do not take a double dose to make up for a missed dose.

2.2 Administration Modification for Concomitant Use with Bile Acid Binding Resins Administer LYNAVOY at least 4 hours before or 4 hours after taking a bile acid binding resin [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] .

Tablets: 40 mg of linerixibat, purple, biconvex, round, film-coated tablets debossed with "GS 3JG" on one side. Tablets: 40 mg ( 3 )

None. None. ( 4 )

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.

Bile Acid Binding Resins : Administer at least 4 hours before or 4 hours after administration of LYNAVOY. ( 7.1 )

7.1 Effects of Bile Acid Binding Resins on LYNAVOY Instruct patients to take LYNAVOY at least 4 hours before or 4 hours after taking a bile acid binding resin [see Dosage and Administration (2.2) ] . Based on in vitro data, bile acid resins may bind linerixibat in the gut [see Clinical Pharmacology (12.3) ]. Concomitant use of bile acid binding resins with LYNAVOY can potentially inhibit the effects of LYNAVOY on the ileal bile acid transporter (IBAT).

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.

Dose-dependent increases in the incidence of gastrointestinal adverse reactions have been observed with LYNAVOY dosages 4.5-fold higher than the recommended dosage. There is no specific antidote for LYNAVOY. If an overdose occurs, discontinue LYNAVOY, monitor the patient for any signs and symptoms and institute general supportive measures as needed. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Risk Summary There are no data on the use of LYNAVOY in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Use of LYNAVOY during pregnancy is expected to result in minimal fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3) ] . Linerixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) , Clinical Considerations ] . In animal reproduction studies, in which linerixibat was administered orally to pregnant rabbits and rats during the period of organogenesis, no malformations or effects on embryo-fetal survival were reported at exposures 470 and 1,100 times the recommended human dose, respectively (see Data ) . The background risk of birth defects and miscarriage for the indicated population is unknown. 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. There is a pregnancy safety study that monitors pregnancy exposures and outcomes in women who have taken LYNAVOY during pregnancy. Pregnant women exposed to LYNAVOY, or their healthcare providers, should report LYNAVOY exposure by contacting Intercept Pharmaceuticals at 1-844-782-4278. Clinical Considerations Fetal/Neonatal Adverse Reactions Linerixibat may inhibit the absorption of fat-soluble vitamins (FSV). FSV are essential for normal fetal growth and development. Monitor pregnant patients for FSV deficiency and supplement as needed. Increased supplementation of FSVs may be needed during pregnancy [see Warnings and Precautions (5.3) ] . Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated orally with linerixibat up to 1,000 mg/kg/day (approximately 1,100 times the recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with linerixibat up to 125 mg/kg/day (approximately 470 times the recommended dose based on AUC) during the period of organogenesis. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with linerixibat up to 1,000 mg/kg/day during organogenesis through lactation. Maternal systemic exposure to linerixibat at the maximum dose tested was approximately 1,100 times the recommended human dose based on AUC.

The safety and efficacy of LYNAVOY have not been established in pediatric patients.

Of the 119 patients that received LYNAVOY in Study 1, 25 (21%) were aged 65 years and older and 3 (3%) were aged 75 years and older [see Clinical Studies (14) ] . No overall differences in safety or effectiveness were observed between patients 65 to less than 75 years of age and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] . Clinical studies of LYNAVOY did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger adult patients.

Linerixibat is an orally administered IBAT inhibitor. Linerixibat has the chemical name 3-((((3 R ,5 R )-3-butyl-3-ethyl-7-methyloxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[ f ][1,4]thiazepin-8-yl)methyl)amino)pentanedioic acid. The molecular formula of linerixibat is C 28 H 38 N 2 O 7 S with a molecular weight of 546.68 g/mol. Linerixibat has the following chemical structure: "*" represent chiral centers. Linerixibat is a white to off-white solid. Its solubility in aqueous solutions is pH-dependent and varies from very slightly to slightly soluble. LYNAVOY is available for oral administration as tablets containing 40 mg linerixibat and the following excipients: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The tablet film-coating contains black iron oxide, hypromellose, polyethylene glycol, red iron oxide, and titanium dioxide. Chemical Structure

Linerixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids in the terminal ileum leading to their increased fecal elimination. Cholestatic pruritus is a common symptom in patients with PBC, and the pathophysiology of pruritus in patients with PBC is not completely understood. Although the complete mechanism by which linerixibat improves pruritus in PBC patients is unknown, it may involve inhibition of the IBAT as observed by a decrease in mediators of pruritus including serum bile acids [see Clinical Pharmacology (12.2) ] .

Linerixibat reduces total serum bile acids in healthy volunteers and PBC patients with cholestatic pruritus. In healthy volunteers, serum bile acids were reduced within 1 day of LYNAVOY treatment compared to placebo treatment. In Study 1, total serum bile acids were reduced from baseline over the 24-week treatment period in the LYNAVOY group when compared to the placebo group.

, Mutagenesis, Impairment of Fertility Carcinogenesis Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day. Mutagenesis Linerixibat was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (rat bone marrow micronucleus) assays. Impairment of Fertility No effects on fertility or early embryonic development were observed in male and female rats treated orally with linerixibat up to 1,000 mg/kg/day.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Administration Instructions Instruct patients to take LYNAVOY at least 30 minutes before any food or beverage (other than water) [see Dosage and Administration (2.1) ] . Instruct patients that if they miss a dose of LYNAVOY to take it as soon as possible and at least 30 minutes before their next meal, then resume the original dosing schedule. If a dose is missed by more than 6 hours, skip the dose and resume the original dosing schedule. Advise patients to not take a double dose to make up for a missed dose [see Dosage and Administration (2.1) ]. Instruct patients to take LYNAVOY at least 4 hours before or 4 hours after taking a bile acid binding resin [see Drug Interactions (7.1) ]. Liver Test Abnormalities Advise patients that their healthcare provider will obtain liver tests before starting LYNAVOY and periodically during treatment with LYNAVOY [see Warnings and Precautions (5.1) ]. Diarrhea Advise patients to monitor for dehydration. Consider interrupting or discontinuing LYNAVOY treatment if diarrhea persists. [see Warnings and Precautions (5.2) ] . Fat-Soluble Vitamin (FSV) Deficiency Advise patients that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting treatment and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3) ] . Inform patients that they may bleed more easily or may bleed longer, and could develop bone fractures. Advise patients to call their healthcare provider for any signs or symptoms of bleeding, or if they have a bone fracture. Pregnancy Inform patients that there is a pregnancy safety study tracking pregnancy exposures and outcomes with LYNAVOY. Ask pregnant women to report LYNAVOY exposure by contacting Intercept Pharmaceuticals at 1-844-782-4278. LYNAVOY is a trademark of GSK Group of Companies licensed to Intercept Pharmaceuticals, Inc.

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture. Keep the bottle tightly closed.