Livmarli

1 INDICATIONS AND USAGE LIVMARLI is an ileal bile acid transporter (IBAT) inhibitor indicated for: • the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). ( 1.1 ) • the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC). ( 1.2 ) o Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of bile salt export pump (BSEP) protein. ( 14.2 ) 1.1 Treatment of Cholestatic Pruritus in Patients with Alagille Syndrome LIVMARLI ® is indicated for the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). 1.2 Treatment of Cholestatic Pruritus in Patients with Progressive Familial Intrahepatic Cholestasis LIVMARLI is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC). Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of bile salt export pump (BSEP) protein [see Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION • Use LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. ( 2.1 ) • Use LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. ( 2.1 ) • LIVMARLI Tablets can be used for treatment of both ALGS and PFIC in patients weighing 25 kg and above who can swallow tablets. ( 2.1 ) ALGS: ○ The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. ○ Starting dose is 190 mcg/kg orally once daily,and should be increased to 380 mcg/kg daily after one week, as tolerated and not to exceed a maximum daily dose of 28.5 mg per day for the oral solution and 30 mg per day for the tablets. ( 2.2 ) PFIC: ○ The recommended dosage is 570 mcg/kg twice daily before a meal. ○ Starting dose is 285 mcg/kg orally once daily in the morning and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated and not to exceed a maximum daily dose of 38 mg per day for the oral solution and 40 mg per day for the tablets. ( 2.3 ) • See full prescribing information for additional dosage details for LIVMARLI oral solution and tablet formulations. ( 2.2 , 2.3 ) 2.1 Important Administration Information • Use LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. • Use LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. • The two strengths of LIVMARLI Oral Solution, 9.5 mg/mL and 19 mg/mL, should not be substituted for one another when treating PFIC patients [see Dosage and Administration (2.3) ]. • LIVMARLI tablets can be used for treatment of both ALGS and PFIC in patients weighing 25 kg and above who can swallow tablets. Select LIVMARLI Oral Solution or LIVMARLI Tablets based on the patient's weight and ability to swallow tablets [see Dosage and Administration (2.2 , 2.3 )]. 2.2 Recommended Dosage for Alagille Syndrome Use LIVMARLI Oral Solution 9.5 mg/ mL or LIVMARLI Tablets for the treatment of ALGS . The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. Start dosing at 190 mcg/kg administered orally once daily; after one week, increase to 380 mcg/kg once daily, as tolerated. The maximum daily dose should not exceed 28.5 mg (3 mL) per day for LIVMARLI Oral solution and 30 mg per day for LIVMARLI tablets. Refer to the dosage by weight guidelines presented in Table 1 for LIVMARLI Oral Solution and Table 2 for LIVMARLI tablets. Table 1: 9.5 mg/mL LIVMARLI Oral Solution for Patients with ALGS: Volume per Dose (mL) by Weight Patient Weight (kg) Days 1-7 (190 mcg/kg once daily) Beginning Day 8 (380 mcg/kg once daily) 9.5 mg/mL Solution (for ALGS) Volume per Dose (mL) 5 to 6 0.1 0.2 7 to 9 0.15 0.3 10 to 12 0.2 0.45 13 to 15 0.3 0.6 16 to 19 0.35 0.7 20 to 24 0.45 0.9 25 to 29 0.5 1 30 to 34 0.6 1.25 35 to 39 0.7 1.5 40 to 49 0.9 1.75 50 to 59 1 2.25 60 to 69 1.25 2.5 70 or higher 1.5 3 Table 2: LIVMARLI Tablets for Patients with ALGS: Dosage by Weight* *Select the appropriate product based on the patient's weight and ability to swallow tablets. Patient Weight (kg) Days 1 to 7 (190 mcg/kg QD) Beginning Day 8 (380 mcg/kg QD) Less than 25 Use Oral Solution Use Oral Solution 25 to 32 10 mg 33 to 43 15 mg 44 to 65 10 mg 20 mg 66 or higher 15 mg 30 mg 2.3 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis Use LIVMARLI Oral Solution 19 mg/mL or LIVMARLI Tablets for the treatment of PFIC . The two strengths of LIVMARLI, 9.5 mg/mL and 19 mg/mL, should not be substituted for one another when treating PFIC patients. Special attention should be given to the accurate calculation of the dose volume of LIVMARLI. This is especially important for pediatric patients less than 5 years old as LIVMARLI oral solution contains the excipient propylene glycol (364.5 mg/mL) [see Warnings and Precautions (5.4) and Overdosage (10) ]. The recommended dosage is 570 mcg/kg twice daily 30 minutes before a meal. The starting dose is 285 mcg/kg orally once daily in the morning, and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated. The maximum daily dose should not exceed 38 mg (2 mL) per day for LIVMARLI oral solution and 40 mg per day for LIVMARLI tablets. Refer to the dosing by weight guidelines presented in Table 3 for LIVMARLI oral solution and Table 4 for LIVMARLI tablets. Table 3: 19 mg/mL LIVMARLI Oral Solution for Patients with PFIC: Volume per Dose (mL) by Weight Patient Weight (kg) 285 mcg/kg (once daily titrated to twice daily) 428 mcg/kg (twice daily) 570 mcg/kg (twice daily as tolerated) 19 mg/mL Solution (for PFIC) Volume per Dose (mL) 5 0.1 0.1 0.15 6 to 7 0.1 0.15 0.2 8 0.1 0.2 0.25 9 0.15 0.2 0.25 10 to 12 0.15 0.25 0.3 13 to 15 0.2 0.3 0.4 16 to 19 0.25 0.4 0.5 20 to 24 0.3 0.5 0.6 25 to 29 0.4 0.6 0.8 30 to 34 0.45 0.7 0.9 35 to 39 0.6 0.8 1 40 to 49 0.6 0.9 1 50 to 59 0.8 1 1 60 or higher 0.9 1 1 Table 4: LIVMARLI Tablets for Patients with PFIC: Dosage by Weight* *Select the appropriate product based on the patient's weight and ability to swallow tablets. Patient Weight (kg) 285 mcg/kg BID 428 mcg/kg BID 570 mcg/kg BID Less than 25 Use Oral Solution Use Oral Solution Use Oral Solution 25 to 32 15 mg 33 to 43 10 mg 15 mg 20 mg 44 or higher 15 mg 20 mg 20 mg 2.4 Missed Dose For once daily dosing: If a dose is missed, it should be taken as soon as possible within 12 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed. For twice daily dosing: If a dose is missed, it should be taken as soon as possible within 6 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 6 hours, the dose can be omitted and the original dosing schedule resumed. 2.5 Important Administration Instructions Administer LIVMARLI oral solution and tablets 30 minutes before a meal [see Clinical Pharmacology (12.3) ] . A calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dosing dispenser) for LIVMARLI oral solution will be provided by the pharmacy to measure and deliver the prescribed dose accurately. After opening the LIVMARLI oral solution bottle, store below 30°C (86°F) and discard any remaining LIVMARLI oral solution after 100 days. 2.6 Dosage Modification for Management of Adverse Events Establish the baseline pattern of variability of liver tests prior to starting LIVMARLI, so that potential signs of liver injury can be identified. Monitor liver tests (e.g., ALT [alanine aminotransferase], AST [aspartate aminotransferase], TB [total bilirubin]), DB [direct bilirubin], and International Normalized Ratio [INR]) during treatment with LIVMARLI. Reduce the dosage or interrupt LIVMARLI if new onset liver test abnormalities occur. Once the liver test abnormalities either return back to baseline values or stabilize at a new baseline value, consider restarting LIVMARLI at the last tolerated dose, and increase the dose as tolerated. Consider discontinuing LIVMARLI permanently if liver test abnormalities recur or symptoms consistent with clinical hepatitis are observed [see Warnings and Precautions (5.1) ] . LIVMARLI has not been studied in patients with hepatic decompensation. Discontinue LIVMARLI permanently if a patient experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). 2.7 Administration Modification for Drug Interaction Bile Acid Binding Resins Administer LIVMARLI at least 4 hours before or 4 hours after administering the bile acid binding resins [see Drug Interactions (7.1) ] when used concomitantly .

4 CONTRAINDICATIONS LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy) [see Warnings and Precautions (5.1) ] . Patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). ( 4 )

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Obtain baseline liver tests and monitor patients frequently for the first 6 to 8 months after starting therapy, and as clinically indicated thereafter during treatment. If liver test abnormalities or signs of clinical hepatitis occur, consider dose reduction or treatment interruption. For persistent or recurrent liver test abnormalities relative to baseline, discontinue LIVMARLI. Monitor patients with compensated cirrhosis frequently. Permanently discontinue LIVMARLI if hepatic decompensation event occurs. ( 5.1 ) • Gastrointestinal Adverse Reactions: Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. ( 5.2 ) • Fat-Soluble Vitamin (FSV) Deficiency: Obtain baseline levels and monitor during treatment. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, consider discontinuing LIVMARLI treatment. ( 5.3 ) o Fracture: Consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. o Bleeding: Interrupt treatment with LIVMARLI. Treatment can be restarted if the FSV deficiency is corrected and bleeding has resolved. • Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 years of Age): Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue if toxicity is suspected. ( 5.4 ) 5.1 Hepatotoxicity LIVMARLI treatment is associated with a potential for drug-induced liver injury. In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died. In the ALGS trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Most abnormalities included elevations in ALT, AST, and/or TB/DB. One patient whose TB was elevated at baseline discontinued LIVMARLI after 28 weeks due to increased TB above baseline. Four patients had ALT increases that led to dose modification (n=1), dose interruption (n=2), or permanent discontinuation (n=2) of LIVMARLI during the long-term, open-label extension period [see Adverse Reactions (6.1) ]. Obtain baseline liver tests because some ALGS and PFIC patients have abnormal liver tests at baseline. Monitor patients frequently for the first 6 to 8 months after starting therapy and as clinically indicated thereafter during treatment with LIVMARLI. Monitor for elevations in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. If liver test abnormalities or signs of clinical hepatitis occur in the absence of other causes, consider dose reduction or treatment interruption. Permanently discontinue LIVMARLI if a patient experiences the following: • persistent or recurrent liver test abnormalities, or • upon rechallenge, signs and symptoms consistent with clinical hepatitis, or • a hepatic decompensation event. The safety and effectiveness of LIVMARLI have not been established in patients with decompensated cirrhosis. Monitor patients with compensated cirrhosis frequently and discontinue LIVMARLI if hepatic decompensation occurs. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Contraindications (4) ] . 5.2 Gastrointestinal Adverse Reactions Diarrhea and abdominal pain were reported as the most common adverse reactions in patients treated with LIVMARLI [see Adverse Reactions (6.1) ] . Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. Monitor for dehydration due to diarrhea and treat promptly. LIVMARLI was not evaluated in PFIC patients with chronic diarrhea requiring intravenous fluids. When diarrhea or abdominal pain resolves, restart LIVMARLI at the last tolerated dose and increase the dose as tolerated. Consider stopping LIVMARLI treatment if they recur upon re-challenge with LIVMARLI. 5.3 Fat Soluble Vitamin (FSV) Deficiency LIVMARLI may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K (measured using INR levels). ALGS and PFIC patients can have FSV deficiency at baseline and are frequently supplemented with FSV. In ALGS patients in Trial 1, treatment-emergent FSV deficiency was reported in 3 (10%) patients during 48 weeks of treatment. In PFIC patients in Trial 2, treatment-emergent FSV deficiency (assessed biochemically) was reported in 13 (28%) of LIVMARLI-treated patients versus 16 (35%) of placebo-treated patients during 26 weeks of treatment. Bone Fracture Treatment-emergent bone fracture events have been observed more frequently with LIVMARLI-treated patients compared to placebo-treated patients [see Adverse Reactions (6.1) ] . If fracture occurs, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. Bleeding If bleeding occurs, interrupt treatment with LIVMARLI. LIVMARLI can be restarted if FSV deficiency is corrected and bleeding has resolved. Obtain serum FSV levels prior to initiation of LIVMARLI 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 LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation. If complications of FSV deficiency occur, such as fracture or bleeding, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels. 5.4 Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age) LIVMARLI oral solution contains propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity, and a safe level for propylene glycol exposure with repeated administration has not been established for pediatric patients less than 5 years of age. When LIVMARLI oral solution is administered at the dose (380 mcg/kg once daily) for treatment of cholestatic pruritus in patients with ALGS, the exposure to propylene glycol will be 14.6 mg/kg/day. When LIVMARLI oral solution is administered at the dose (570 mcg/kg twice daily) for treatment of cholestatic pruritus in patients with PFIC, the exposure to propylene glycol will be 21.9 mg/kg/day. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of potential propylene glycol toxicity, including hemolysis, hyperosmolarity with anion gap metabolic acidosis, acute kidney injury, and CNS toxicity. Discontinue LIVMARLI oral solution if propylene glycol toxicity is suspected [see Overdosage (10) ].

7 DRUG INTERACTIONS • Bile Acid Sequestrants: Modify LIVMARLI administration schedule. ( 7.1 ) 7.1 Effects of Other Drugs on LIVMARLI Bile Acid Binding Resins Bile acid binding resins may bind to maralixibat in the gut. Administer LIVMARLI at least 4 hours before or 4 hours after administration of bile acid binding resins (e.g., cholestyramine, colesevelam, or colestipol). 7.2 Effects of LIVMARLI on Other Drugs OATP2B1 substrates Maralixibat is an OATP2B1 inhibitor based on in vitro studies. A decrease in the oral absorption of OATP2B1 substrates (e.g., statins) due to OATP2B1 inhibition in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates (e.g. statins) as needed [see Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] • Fat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥5%) are: • ALGS: diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures. ( 6.1 ) • PFIC: diarrhea, fat soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mirum Pharmaceuticals at 1-855-MRM-4YOU 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. ALGS: In the Alagille syndrome clinical development program, which includes five clinical studies comprising 86 patients, patients received doses of LIVMARLI up to 760 mcg/kg per day with a median duration of exposure of 32.3 months (range: 0.03 – 60.9 months). In Trial 1, the 4-week placebo control period occurred after 18 weeks of LIVMARLI treatment. In two supportive studies that included long-term open‑label extensions, only 13 weeks of placebo-controlled treatment occurred which evaluated doses lower than 380 mcg/kg/day. The majority of LIVMARLI exposure in the development program occurred without a placebo control in open-label trial extensions. The most common adverse reactions (≥5%) for ALGS patients treated with LIVMARLI are presented in Table 5 below. Treatment interruptions or dose reductions occurred in 5 (6%) patients due to diarrhea, abdominal pain, or vomiting. Table 5: Adverse Reactions Occurring in ≥ 5% of Patients Treated with LIVMARLI in the ALGS Clinical Development Program *Terms were defined as: Fat-Soluble Vitamin deficiency includes: A, D, E, or K deficiency, or INR increase Abdominal Pain includes : abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper Transaminases increased includes : ALT abnormal, ALT increased, AST abnormal, AST increased Bone Fracture includes: tibia fracture, rib fracture, hand fracture, humerus fracture, pathological fracture, forearm fracture, clavicle fracture 1 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patient LIVMARLI (n=86) Adverse Reaction Any Grade n (%) Number of events per 100 person‑years 1 Diarrhea 48 (55.8%) 41.6 Abdominal pain* 46 (53.5%) 38.6 Vomiting 35 (40.7%) 19.8 Nausea 7 (8.1%) 2.9 Fat-Soluble Vitamin deficiency* 22 (25.6%) 11.1 Transaminases increased (ALT, AST)* 16 (18.6%) 6.9 Bone Fractures* 8 (9.3%) 3.3 Liver Test Abnormalities Increase in Transaminases In a pooled analysis of patients with ALGS (N=86) administered LIVMARLI, increases in hepatic transaminases (ALT) were observed. Seven (8.1%) patients discontinued LIVMARLI due to ALT increases. Three (3.5%) patients had a decrease in dose or interruption of LIVMARLI in response to ALT increases. In the majority of cases, the elevations resolved or improved after discontinuation or dose modification of LIVMARLI. In some cases, the elevations resolved or improved without change in LIVMARLI dosing. Increases to more than three times baseline in ALT occurred in 26% of patients treated with LIVMARLI and increases to more than five times baseline occurred in 3%. AST increases to more than three times baseline occurred in 16% of patients treated with LIVMARLI, and an increase to more than five times baseline occurred in one patient. Elevations in transaminases were asymptomatic and not associated with bilirubin elevations or other laboratory abnormalities. Increases in Bilirubin Four (4.6%) patients in the pooled analysis experienced bilirubin increases above baseline, and LIVMARLI was subsequently withdrawn in two of these patients, who had elevated bilirubin at baseline. PFIC: In Trial 2, which enrolled 93 patients, 47 patients received doses of LIVMARLI up to 570 mcg/kg BID, with a median duration of exposure of 6 months (range: 0.3-6.7 months). The most common adverse reactions (≥5%) for PFIC patients treated with LIVMARLI at a rate greater than placebo are presented in Table 6 below. Diarrhea was the most frequent adverse reaction; the majority of episodes were mild and transient with a median duration of 5.5 days. Nineteen (40.4%) LIVMARLI-treated subjects had diarrhea greater than or equal to 7 days. Placebo-treated subjects had a median duration of 3 days of diarrhea and two subjects (4.3%) experienced diarrhea with a duration greater than or equal to 7 days. There were no severe events reported. The majority of abdominal pain events were mild based on AE grading, and associated with concurrent diarrhea. One LIVMARLI-treated patient with an event of mild diarrhea discontinued treatment. Treatment interruptions or dose reductions occurred in 3 (6.4%) LIVMARLI-treated patients due to diarrhea or abdominal pain. No placebo-treated subjects discontinued treatment or had dose reductions or interruptions due to diarrhea. Table 6: Adverse Reactions (any grade) Occurring in ≥5% and at a Rate Greater Than Placebo in Patients Treated with LIVMARLI in the PFIC Trial † Terms were defined as: Abdominal Pain includes : abdominal pain, abdominal pain upper, abdominal distension Transaminases increased includes : Hypertransaminasaemia, ALT abnormal, ALT increased, AST abnormal, AST increased, Transaminases increased, Hepatic enzyme increased. Bone Fracture includes : upper limb fracture, lower limb fracture, radius fracture, ulna fracture, femur fracture, foot fracture Adverse Reaction (Any Grade) Placebo n=46 LIVMARLI n=47 Diarrhea 9 (19.6%) 27 (57.4%) Abdominal pain † 7 (15.2%) 13 (27.7%) Transaminases increased (ALT or AST) † 3 (6.5%) 8 (17%) Hematochezia or rectal hemorrhage 1 (2.2%) 4 (8.5%) Bone Fractures † 0 3 (6.4%) Hepatotoxicity LIVMARLI treatment is associated with a potential for drug-induced liver injury. In PFIC patients in Trial 2, treatment-emergent elevations of liver tests or worsening of liver tests, relative to baseline values, and hepatic decompensation events were observed. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI; one patient received 570 mcg/kg twice daily and the second patient required dose interruption and reduction. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died. Biliary Complications In the placebo-controlled portion of Trial 2, two LIVMARLI-treated patients developed cholangitis or cholecystitis within 3-weeks of drug discontinuation (after 84 days and 130 days after initiating LIVMARLI treatment, respectively). Four LIVMARLI-treated patients developed cholecystitis or cholangitis in the open-label extension portion of Trial 2; the average time to onset was 281 days. Bone Fracture In PFIC patients in Trial 2, treatment-emergent bone fracture events were observed. Three receiving LIVMARLI experienced bone fractures relative to none in placebo-treated patients. The median time to onset of fractures was 73 days. Two LIVMARLI-treated patients developed bone fractures in the open-label portion of Trial 2, with average time to onset of fracture was 204 days. Bleeding In PFIC patients in Trial 2, treatment-emergent events of hematochezia (4 [8.5%] versus 1 [2.2%]), decrease in hemoglobin greater than or equal to 2 grams/dL from baseline (8 [17%] versus 1 [2.2%]), were reported more frequently in LIVMARLI-treated patients relative to placebo-treated patients 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LIVMARLI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhage General disorders and administration site conditions: drug ineffective Injury, poisoning and procedural complications : off label use Investigations : gamma-glutamyltransferase increased Nervous system disorders : intracranial hemorrhage

8.1 Pregnancy Risk Summary Maternal use at the recommended clinical dose of LIVMARLI is not expected to result in measurable fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3) ]. Maralixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) and Clinical Considerations ] . In animal reproduction studies, no developmental effects were observed (see Data ) . The estimated background risk of major birth defects for ALGS is higher than the general population because ALGS is an autosomal dominant condition. The background risk of miscarriage for ALGS is unknown. The background risk of birth defects and miscarriage for PFIC 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Maralixibat may inhibit the absorption of fat-soluble vitamins (FSV). Monitor 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 up to 1000 mg/kg/day (approximately 3300 to 12000 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to 250 mg/kg/day (approximately 1200 to 4700 times the maximum 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 up to 750 mg/kg/day during organogenesis through lactation. Maternal systemic exposure to maralixibat at the maximum dose tested was approximately 2500 to 9400 times the maximum recommended dose based on AUC.