Maralixibat Chloride

• 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 .

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) ].

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.

8.2 Lactation Risk Summary LIVMARLI has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to LIVMARLI at the recommended dose [see Clinical Pharmacology (12.3) ] . There are no data on the presence of LIVMARLI in human milk, the effects on the breastfed infant, or the effects on milk production. Patients with ALGS or PFIC can have FSV deficiency as part of their disease. Maralixibat may reduce absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) ] . Monitor FSV levels and supplement FSV intake, if FSV deficiency is observed during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition.

8.4 Pediatric Use ALGS The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged 3 months of age and older. Use of LIVMARLI in this population is supported by evidence from a study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period. Additional safety information was obtained from four studies in patients up to 21 years of age (N=55) [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . Use of LIVMARLI in patients 3 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed a similar safety, tolerability and pharmacokinetic profile to patients with ALGS > 12 months of age. The safety and effectiveness of LIVMARLI have not been established in patients with ALGS less than 3 months of age. PFIC The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in PFIC have been established in pediatric patients aged 12 months of age and older. Use of LIVMARLI in this population is supported by evidence from Trial 2 in patients 1 to <18 years of age that included 26 weeks of placebo-controlled safety and efficacy data [see Adverse Reactions (6.1) and Clinical Studies (14.2) ] . The 19 mg/mL formulation of LIVMARLI should be used in patients with PFIC in order to minimize exposure to excipients, including propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity [see Warnings and Precautions (5.4) ] . The safety and effectiveness of LIVMARLI have not been established in patients with PFIC younger than 12 months of age.

8.5 Geriatric Use The safety and effectiveness of LIVMARLI for the treatment of pruritus in ALGS or PFIC in adult patients, 65 years of age and older, have not been established.

8.6 Hepatic impairment Clinical studies of LIVMARLI included ALGS or PFIC patients with impaired hepatic function at baseline. The efficacy and safety in ALGS or PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis have not been established. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Dosage and Administration (2.5) , Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Studies (14) ].

12.1 Mechanism of Action Maralixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum . Pruritus is a common symptom in patients with ALGS or PFIC and the pathophysiology of pruritus in patients with ALGS or PFIC is not completely understood. Although the complete mechanism by which maralixibat improves pruritus in ALGS or PFIC patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids [see Clinical Pharmacology (12.2) ] .

12.2 Pharmacodynamics ALGS In Trial 1, pediatric patients with ALGS were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period [see Clinical Studies (14.1) ] . At baseline, serum bile acids were highly variable among patients ranging from 20 to 749 µmol/L and mean (SD) serum bile acid level was 283 (210.6) µmol/L. Serum bile acid levels decreased from baseline in the majority of patients as early as at Week 12 and the reduction in serum bile acids was generally maintained for the treatment period. PFIC In Trial 2, pediatric patients with PFIC were administered LIVMARLI 570 mcg/kg or placebo twice daily for up to 22 weeks after an initial 4–6-week dose escalation period [see Clinical Studies (14.2) ] . At baseline, serum bile acids concentrations were highly variable among patients ranging from 4 to 504 µmol/L and mean (SD) serum bile acid level was 253 (136) µmol/L. Serum bile acid concentrations decreased from baseline in the majority of patients as early as at Week 2; while the concentrations fluctuated, the reduction in serum bile acids was generally maintained for the treatment period.

12.3 Pharmacokinetics Because of the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Concentrations of maralixibat in the pediatric ALGS and PFIC patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples. Following single dose administration of maralixibat oral solution in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated. Following single dose administration of 30 mg maralixibat oral solution under fasted condition, median Tmax was 0.75 hour and mean (SD) Cmax and AUClast were 1.65 (1.10) ng/mL and 3.43 (2.13) ng·h/mL, respectively. Absorption Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Oral Solution : Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg. No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once-daily. Tablet: After a single 100 mg dose of maralixibat tablet under fasted condition, mean (SD) AUCinf and Cmax were 13.2 (8.2) ng·h/mL and 3.0 (2.2) ng/mL, respectively. Following a single dose of maralixibat oral solution (99.75 mg) under the same conditions, mean (SD) AUCinf and Cmax were 18.4 (13.2) ng·h/mL and 4.3 (2.7) ng/mL, respectively. Given the local site of action of maralixibat, the slightly lower exposure afforded by the tablet compared to the oral solution is not clinically meaningful. Effect of Food Concomitant administration of a high-fat meal with a single dose of maralixibat oral solution decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions. The effect of food on the changes of systemic exposures to maralixibat is not clinically significant [see Dosage and Administration (2.1 , 2.3 )] . Distribution Maralixibat shows high binding (91%) to human plasma proteins in vitro. Elimination Following a single dose of 30 mg maralixibat oral solution in healthy adults, the mean half-life (t 1/2 ) was 1.6 hours. Metabolism No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following administration of [ 14 C]maralixibat as an oral solution. Excretion Fecal excretion was found to be the major route of elimination. Following a single dose of 5 mg 14 C-maralixibat as an oral solution, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. 94% of the fecal excretion was as unchanged maralixibat. Specific Populations Patients with Renal Impairment The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis. Drug Interaction Studies Effect of Other Drugs on Maralixibat Maralixibat is not a substrate of the drug transporters MDR1 (P-gp), BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant drug products are not predicted to affect the disposition of maralixibat. Effect of Maralixibat on Other Drugs In vitro, maralixibat did not induce CYP isoforms 1A2, 2B6, or 3A4, nor inhibit CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations. Maralixibat inhibits CYP3A4 in vitro, however clinically relevant effects on the pharmacokinetics of CYP3A4 substrates are unlikely. In vitro, maralixibat did not inhibit the transporters MDR1 (P-gp), BCRP, OAT1, OAT3, OATP1B1, OATP1B3, PEPT1, OCT1, OCT2, OCT3, OCTN1, OCTN2, MRP2, MATE1, or MATE2-K at clinically relevant concentrations. Maralixibat inhibits the drug transporter OATP2B1 in vitro, which can potentially result in reduced absorption of drugs that rely on OATP2B1-mediated uptake in the GI tract. In clinical studies coadministration of 4.75 mg maralixibat (once daily in the morning) with daily doses of either simvastatin, or lovastatin in the evening, did not have a clinically relevant effect on the pharmacokinetics of these statins and their metabolites. Coadministration of 4.75 mg maralixibat did not affect pharmacokinetics of atorvastatin. However, the effect of maralixibat on the pharmacokinetics of OATP2B1 substrates at higher doses has not been evaluated in a clinical study.

12.5 Pharmacogenomics PFIC is a heterogenous disease caused by homozygous or compound heterozygous variants, with different PFIC subtypes occurring in the general population. PFIC1 is caused by variants in the aminophospholipid flippase (ATP8B1) gene, which encodes the Familial Intrahepatic Cholestasis 1 (FIC1) protein, while PFIC2 results from variants in the ABCB11 gene, which encodes the Bile Salt Export Pump (BSEP) protein. PFIC2 is further categorized into BSEP subgroups based on specific variants. The BSEP-1 subgroup includes patients with at least one p.D482G (c.1445A>G) or p.E297G (c.890A>G) variant, BSEP-2 includes patients with at least one missense variant other than p.D482G or p.E297G (non BSEP-1), and BSEP-3 includes patients with variants that are predicted to encode a non-functional protein. PFIC3 is caused by variants in the ABCB4 gene, which encodes multidrug resistance protein 3 (MDR3). PFIC4 is caused by variants in the tight junction protein 2 gene (TJP2), which encodes TJP2. PFIC6 is caused by variants in myosin 5B (MYO5B), which encodes MYO5B. Patients can be clinically diagnosed with PFIC without a known pathogenic variant. PFIC2 is the most common subtype accounting for 37-90% of patients with PFIC. The prevalence of BSEP-1, BSEP-2, and BSEP-3 subgroups are approximately 27.3%, 51.5%, and 21.2%, respectively, based on data from a global consortium characterizing the natural history of severe BSEP deficiency.