CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Alagille Syndrome. The efficacy of LIVMARLI was assessed in Trial (NCT02160782), which consisted of an 18-week open-label treatment period; 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; subsequent 26-week open-label treatment period; and long-term open-label extension period.Thirty-one pediatric ALGS patients with cholestasis and pruritus were enrolled, with 90.3% of patients receiving at least one medication to treat pruritus at study entry. All patients had JAGGED1 mutation. Patients were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period; two patients discontinued treatment during this first 18 weeks of open-label treatment. The 29 patients who completed the open-label treatment phase were then randomized to continue treatment with LIVMARLI or receive matching placebo during the 4-week drug withdrawal period at Weeks 19-22 (n=16 placebo, n=13 LIVMARLI). All 29 patients completed the randomized, blinded drug withdrawal period; subsequently, patients received open-label LIVMARLI at 380 mcg/kg once daily for an additional 26 weeks.Randomized patients had median age of years (range: to 15 years) and 66% were male. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid levels 280 (213) umol/L, AST 158 (68) U/L, ALT 179 (112) U/L, Gamma Glutamyl Transferase (GGT) 498 (399) U/L, and TB 5.6 (5.4) mg/dL.Given the patients young age, single-text observer-reported outcome was used to measure patients pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]). Pruritus symptoms were assessed on 5-point ordinal response scale, with scores ranging from (none observed or reported) to (very severe). Patients were included in Trial if their average pruritus score was greater than 2.0 (moderate) in the weeks prior to baseline.The average of the worst daily ItchRO(Obs) pruritus scores was computed for each week. For randomized patients, the mean (SD) at baseline (pre-treatment) was 3.1 (0.5) and the mean (SD) at Week 18 (pre-randomized withdrawal period) was 1.4 (0.9). On average, patients administered LIVMARLI for 22 weeks maintained pruritus reduction whereas those in the placebo group who were withdrawn from LIVMARLI after Week 18 returned to baseline pruritus scores by Week 22. Results from the placebo-controlled period are presented in Table 7. After re-entering the open-label treatment phase, both randomized treatment groups had similar mean pruritus scores by Week 28, the first week placebo patients received the full dosage of LIVMARLI after withdrawal. These observer-rated pruritus results are supported by similar results on patient-rated pruritus in patients years of age and older who were able to self-report their itching severity.Table 7: Weekly Average of Worst Daily ItchRO(Obs) Pruritus Severity Scores in Trial 1Results based on an analysis of covariance model with treatment group and Week 18 average worst daily pruritus score as covariatesMaralixibat(N=13)Placebo(N=16)Mean DifferenceWeek 22, Mean (95% CI)1.6 (1.1, 2.1)3.0 (2.6, 3.5)Change from Week 18 to Week 22, Mean (95% CI) 0.2 (-0.3, 0.7)1.6 (1.2, 2.1)-1.4 (-2.1, -0.8). 14.2 Progressive Familial Intrahepatic Cholestasis. The efficacy of LIVMARLI was assessed in Trial (NCT03905330), 26-week randomized, placebo-controlled trial.Efficacy was evaluated in 64 patients with documented molecular diagnosis of PFIC with presence of biallelic known pathogenic variants; this included 31 non-truncated PFIC2 patients (i.e., excluding patients with BSEP3) and 33 patients with PFIC1 (n=13), PFIC3 (n=9), PFIC4 (n=7), or PFIC6 (n=4) [see Clinical Pharmacology (12.5)]. Additional patients with BSEP3 (n=9), prior surgical diversion (n=8), heterozygous subjects (n=2), or no variants associated with cholestasis (n=8) were included for evaluation in supplemental cohort [see Adverse Reactions (6.1)]. Patients were randomized to receive maralixibat orally 570 mcg/kg (n=33) or placebo (n=31) twice daily. 53% of pediatric patients were females. Most patients were on stable ursodeoxycholic acid (89.1%) or rifampicin (51.6%) therapy at baseline. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid levels 263 (143) umol/L, AST 113 (82) U/L, ALT 107 (87) U/L, and TB 4.1 (4.1) mg/dL, DB 3.0 (3.1) mg/dL.Given the patients young age, single-text observer-reported outcome was used to measure patients pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]). Pruritus symptoms were assessed on 5-point ordinal response scale, with scores ranging from (none observed or reported) to (very severe). Patients were included in Trial if their average pruritus score was greater than or equal to 1.5 in the weeks prior to baseline.Table presents the results of the comparison between LIVMARLI and placebo on the mean change in the average morning ItchRO(Obs) severity score between baseline and Weeks 15-26. For the outcome summarized over Weeks 15-26, the average morning ItchRO(Obs) severity score for each patient was calculated by: (Step 1) averaging the morning scores within week; (Step 2) averaging weekly morning scores to yield single 4-week score; and finally (Step 3) averaging the three 4-week average morning scores (Weeks 15-18, Weeks 19-22, Weeks 23-26). The baseline average itching scores for each patient was calculated by averaging the morning ItchRO(Obs) score obtained in Step across the weeks prior to the first dose of the study. Patients treated with LIVMARLI demonstrated greater improvement in pruritus compared with placebo.Table 8: Average Morning ItchRO(Obs) Pruritus Severity Scores in Trial 2aResults based on least squares means from an analysis of mixed-effect model for repeated measures (MMRM). Model adjusts for treatment group, visit, treatment group-by-visit interaction, baseline 4-week average morning ItchRO(Obs) severity score, baseline score-by-visit interaction, and PFIC type.Maralixibat(N=33)Placebo(N=31)Baseline Mean2.92.7Change from baseline to Weeks 15-26a Mean (95% CI)-1.8 (-2.2, -1.4)-0.6 (-1.0, -0.2)Mean difference from Placebo (95% CI)-1.2 (-1.7, -0.7)p-value<0.0001Figure displays the means (95% confidence intervals) of patients average morning ItchRO(Obs) severity scores in each treatment group for each 4-6 week time period.Figure 1. Mean of the Average Morning ItchRO(Obs) Pruritus Severity Scores Over Time in PFIC 1, 2, 3, 4, and 6Note: Figure presents least squares mean (95% CI) estimates from mixed model for repeated measures (MMRM) with observed value as the dependent variable and fixed categorical effects of treatment group, time period, treatment-by-time period interaction, and PFIC type.Although the number of patients with BSEP3 in Trial were limited, improvement in pruritus was not observed in patients with BSEP3 who received LIVMARLI compared to patients with BSEP3 who received placebo for 26 weeks.. Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 placebo control in open-label trial extensions.The most common adverse reactions (>=5%) for ALGS patients treated with LIVMARLI are presented in Table below. Treatment interruptions or dose reductions occurred in (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 ProgramTerms were defined as: Fat-Soluble Vitamin deficiency includes: A, D, E, or 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 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patientLIVMARLI (n=86)Adverse ReactionAny Graden (%)Number of events per 100 person-years1 Diarrhea 48 (55.8%)41.6Abdominal pain 46 (53.5%)38.6Vomiting 35 (40.7%)19.8Nausea (8.1%)2.9Fat-Soluble Vitamin deficiency 22 (25.6%)11.1Transaminases increased (ALT, AST) 16 (18.6%)6.9Bone Fractures8 (9.3%)3.3Liver Test AbnormalitiesIncrease in TransaminasesIn 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 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 BilirubinFour (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 median duration of exposure of months (range: 0.3-6.7 months).The most common adverse reactions (>=5%) for PFIC patients treated with LIVMARLI at rate greater than placebo are presented in Table below. Diarrhea was the most frequent adverse reaction; the majority of episodes were mild and transient with median duration of 5.5 days. Nineteen (40.4%) LIVMARLI-treated subjects had diarrhea greater than or equal to days. Placebo-treated subjects had median duration of days of diarrhea and two subjects (4.3%) experienced diarrhea with duration greater than or equal to 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 (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 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 distensionTransaminases 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 fractureAdverse Reaction(Any Grade)Placebon=46LIVMARLIn=47Diarrhea9 (19.6%)27 (57.4%)Abdominal pain+ (15.2%)13 (27.7%)Transaminases increased (ALT or AST) 3 (6.5%)8 (17%)Hematochezia or rectal hemorrhage (2.2%)4 (8.5%)Bone Fractures+ 03 (6.4%)HepatotoxicityLIVMARLI treatment is associated with 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 ComplicationsIn 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 FractureIn 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.BleedingIn PFIC patients in Trial 2, treatment-emergent events of hematochezia (4 [8.5%] versus [2.2%]), decrease in hemoglobin greater than or equal to grams/dL from baseline (8 [17%] versus [2.2%]), were reported more frequently in LIVMARLI-treated patients relative to placebo-treated patients.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USELIVMARLI(R) [liv-MAR-lee](maralixibat)oral solutionThis Instructions for Use contains information on how to take LIVMARLI. Read this Instructions for Use before you start taking LIVMARLI for the first time and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. LIVMARLI is available in two strengths:oLIVMARLI 9.5 mg/mL is for the treatment of Alagille Syndrome.oLIVMARLI 19 mg/mL is for the treatment of Progressive Familial Intrahepatic Cholestasis.Follow your healthcare providers instructions for the dose of LIVMARLI to give.Ask your healthcare provider or pharmacist if you have questions about how to prepare or give the prescribed dose of LIVMARLI. Important information about measuring LIVMARLIoBefore you give LIVMARLI for the first time, talk to your healthcare provider or pharmacist about how to correctly measure your prescribed dose.oYou may be given or more dosing dispensers of different sizes as shown in Table below. Always use the correct dosing dispenser size provided with LIVMARLI based on your current prescribed dose.Table 1Dose (mL)Dosing dispenser size (mL)0.1 to 0.50.50.6 to 111.25 to 33oYour prescribed dose may change over time. Use the table above to choose the correct dosing dispenser size for your prescribed dose.oIf you do not have the correct dosing dispenser size for your prescribed dose, contact your healthcare provider or pharmacist.oThe dosing dispenser may be used for 100 days if cleaned correctly (see Section C). After 100 days, replace the dosing dispenser with new one. new replacement dosing dispenser may be used within the 100 days if necessary.oDo not use household teaspoon or any other dosing device to measure the dose.oDo not open more than bottle of LIVMARLI at time.oDo not give more than the prescribed dose.oDo not use LIVMARLI after 100 days of first opening the bottle or after the throw away (discard) date listed on the pharmacy label (see Section D).oWhen you start new bottle of LIVMARLI, use new dosing dispenser.Storage informationoStore unopened LIVMARLI at room temperature, between 68F and 77F (20C and 25C).oAfter opening the LIVMARLI bottle, store below 86F (30C) and throw away (discard) any remaining LIVMARLI after 100 days.oStore the dosing dispenser in clean, dry place when not in use.Keep LIVMARLI and all medicines out of the reach of children. You will receiveLIVMARLI oral solutionEach package of LIVMARLI contains: LIVMARLI (9.5 mg/mL or 19 mg/mL): Dosing dispensers, provided separately by your pharmacist: Note: Dosing dispenser sizes shown are for example only. Section A: Prepare the bottle1. Remove the LIVMARLI bottle from the box (See Figure A).Note: The LIVMARLI bottle may not be in box. Figure 2. Write the date (bottle open date) on the LIVMARLI bottle (See Figure B).Note: The date of first opening or throw away (discard) date may already be written on the bottle label by your pharmacist. Figure 3. Remove the plastic seal from the bottle (See Figure C).Note: Your pharmacist may have already removed the plastic seal from the bottle. Figure Section B: Prepare and give LIVMARLIStep 1: Draw the dose1.1:Open the bottle by pushing down firmly on the child-resistant cap and turning the cap to the left (counter-clockwise) (See Figure D). Do not throw away the child-resistant cap.Figure 1.2:If using new dosing dispenser, remove the dosing dispenser from the wrapper (See Figure E). Throw away (dispose of) the wrapper in household trash. Figure EIf using used dosing dispenser, make sure the dosing dispenser has been cleaned (See Section C). If there is cap on the dosing dispenser, remove it and throw away (dispose of) the cap into the household trash (See Figure F).Important:oMake sure you use the correct dosing dispenser size for your prescribed dose (See Table 1).oAfter 100 days, replace with new dosing dispenser provided. new replacement dosing dispenser may be used within the 100 days if necessary.oCheck the dosing dispenser for any damage to the barrel, plunger or tip (See Figure G). If you cannot see the dosage marking or if it becomes hard to move the plunger, replace with new dosing dispenser.Note: You can mark the prescribed dose on the dosing dispenser with thin permanent marker to draw up the prescribed dose more easily.Figure FFigure G1.3: Push the plunger down fully to remove air from the dosing dispenser (See Figure H).Figure 1.4:Make sure the cap is removed from bottle and insert the tip of the dosing dispenser into the bottle. The tip of the dosing dispenser should fit securely into the hole of the bottle (See Figure I).Figure 1.5:Keep the dosing dispenser in place and turn the bottle upside down (See Figure J).Figure 1.6:Pull back the plunger slowly until the top of the plunger is even with the marking on the barrel of the dosing dispenser for your prescribed dose of LIVMARLI (See Figure K).See Figure on how to align the plunger with your prescribed dose. Note: The medicine should appear colorless to light yellow and clear. If it is not, do not use the medicine and contact your pharmacist.Figure KFigure LNote: Your dose may be different than the dose shown in the figures. 1.7:Check the dosing dispenser for air bubbles. If you see any air bubbles, fully push the plunger so that the medicine flows back into the bottle and withdraw the prescribed dose (See Figure M).Figure 1.8:When you have measured the correct dose, leave the dosing dispenser in the bottle, and turn the bottle right side up (See Figure N).Figure N1.9:Carefully remove the dosing dispenser from the bottle by pulling straight up on the barrel of the dosing dispenser (See Figure O). Do not push the dosing dispenser plunger during this step.Figure OStep 2: Give the doseNote: LIVMARLI should be taken while sitting up or standing. After taking LIVMARLI wait few minutes before lying down. 2.1:Place the tip of the dosing dispenser against the inside of the cheek (See Figure P) and slowly push the plunger all the way in to give the entire dose of LIVMARLI (See Figure Q).Figure PFigure 2.2:Swallow the dose. If you are not sure the entire dose was swallowed, do not give another dose. Wait until the next scheduled dose.2.3:Place the child-resistant cap back on the bottle and turn the cap to the right (clockwise) (See Figure R).Figure Section C: Cleaning instructions for the dosing dispenserStep 1: Rinse dosing dispenser1.1:Fill cup with water (See Figure S).Figure 1.2:Clean the dosing dispenser by pulling back on the plunger slowly to fill the dosing dispenser with water from the cup (See Figure T).Figure 1.3:Over sink, push the water out of the dosing dispenser (See Figure U). Repeat several times to make sure that all of the LIVMARLI has been removed.Figure UStep 2: Dry the dosing dispenser2.1:Remove the plunger from the barrel of the dosing dispenser by pulling the plunger and barrel away from each other (See Figure V).Figure 2.2:Shake off excess water (See Figure W).Figure 2.3:Place the plunger and barrel on clean, dry paper towel to air dry. Store the dosing dispenser in clean, dry place until your next dose (See Figure X).Figure Before you give the next dose, put the dosing dispenser back together by pushing the plunger into the barrel (See Figure Y).Figure Section D: DisposaloThrow away (dispose of) the bottle of LIVMARLI following the steps below 100 days after first opened or after the throw away (discard) date listed on the pharmacy label, even if there is still medicine in it. 1.Mix medicine with substance such as dirt, cat litter, or used coffee grounds.2.Place the mixture in container such as sealed plastic bag.3.Delete all personal information on the prescription label of the empty medicine bottle, then throw away (dispose of) in the household trash or recycle the empty bottle.oThrow away (dispose of) used dosing dispensers in the household trash.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: July 2024LB00203 LB00212. oLIVMARLI 9.5 mg/mL is for the treatment of Alagille Syndrome.. oLIVMARLI 19 mg/mL is for the treatment of Progressive Familial Intrahepatic Cholestasis.. oBefore you give LIVMARLI for the first time, talk to your healthcare provider or pharmacist about how to correctly measure your prescribed dose.. oYou may be given or more dosing dispensers of different sizes as shown in Table below. Always use the correct dosing dispenser size provided with LIVMARLI based on your current prescribed dose.. oYour prescribed dose may change over time. Use the table above to choose the correct dosing dispenser size for your prescribed dose.. oIf you do not have the correct dosing dispenser size for your prescribed dose, contact your healthcare provider or pharmacist.. oThe dosing dispenser may be used for 100 days if cleaned correctly (see Section C). After 100 days, replace the dosing dispenser with new one. new replacement dosing dispenser may be used within the 100 days if necessary.. oDo not use household teaspoon or any other dosing device to measure the dose.. oDo not open more than bottle of LIVMARLI at time.. oDo not give more than the prescribed dose.. oDo not use LIVMARLI after 100 days of first opening the bottle or after the throw away (discard) date listed on the pharmacy label (see Section D).. oWhen you start new bottle of LIVMARLI, use new dosing dispenser.. oStore unopened LIVMARLI at room temperature, between 68F and 77F (20C and 25C).. oAfter opening the LIVMARLI bottle, store below 86F (30C) and throw away (discard) any remaining LIVMARLI after 100 days.. oStore the dosing dispenser in clean, dry place when not in use.. oMake sure you use the correct dosing dispenser size for your prescribed dose (See Table 1).. oAfter 100 days, replace with new dosing dispenser provided. new replacement dosing dispenser may be used within the 100 days if necessary.. oCheck the dosing dispenser for any damage to the barrel, plunger or tip (See Figure G). If you cannot see the dosage marking or if it becomes hard to move the plunger, replace with new dosing dispenser.. oThrow away (dispose of) the bottle of LIVMARLI following the steps below 100 days after first opened or after the throw away (discard) date listed on the pharmacy label, even if there is still medicine in it. 1.Mix medicine with substance such as dirt, cat litter, or used coffee grounds.2.Place the mixture in container such as sealed plastic bag.3.Delete all personal information on the prescription label of the empty medicine bottle, then throw away (dispose of) in the household trash or recycle the empty bottle.. 1.Mix medicine with substance such as dirt, cat litter, or used coffee grounds.. 2.Place the mixture in container such as sealed plastic bag.. 3.Delete all personal information on the prescription label of the empty medicine bottle, then throw away (dispose of) in the household trash or recycle the empty bottle.. oThrow away (dispose of) used dosing dispensers in the household trash.. Image. Image. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. Figure O. Figure P. Figure Q. Figure R. Figure S. Figure T. Figure U. Figure V. Figure W. Figure X. Figure Y.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in labeling:oHepatotoxicity [see Warnings and Precautions (5.1)]oGastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)]oFat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3)]. oHepatotoxicity [see Warnings and Precautions (5.1)]. oGastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)]. oFat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3)]. Most common adverse reactions (>=5%) are:oALGS: diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures. (6.1)oPFIC: 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.. oALGS: diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures. (6.1). oPFIC: diarrhea, fat soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 placebo control in open-label trial extensions.The most common adverse reactions (>=5%) for ALGS patients treated with LIVMARLI are presented in Table below. Treatment interruptions or dose reductions occurred in (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 ProgramTerms were defined as: Fat-Soluble Vitamin deficiency includes: A, D, E, or 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 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patientLIVMARLI (n=86)Adverse ReactionAny Graden (%)Number of events per 100 person-years1 Diarrhea 48 (55.8%)41.6Abdominal pain 46 (53.5%)38.6Vomiting 35 (40.7%)19.8Nausea (8.1%)2.9Fat-Soluble Vitamin deficiency 22 (25.6%)11.1Transaminases increased (ALT, AST) 16 (18.6%)6.9Bone Fractures8 (9.3%)3.3Liver Test AbnormalitiesIncrease in TransaminasesIn 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 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 BilirubinFour (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 median duration of exposure of months (range: 0.3-6.7 months).The most common adverse reactions (>=5%) for PFIC patients treated with LIVMARLI at rate greater than placebo are presented in Table below. Diarrhea was the most frequent adverse reaction; the majority of episodes were mild and transient with median duration of 5.5 days. Nineteen (40.4%) LIVMARLI-treated subjects had diarrhea greater than or equal to days. Placebo-treated subjects had median duration of days of diarrhea and two subjects (4.3%) experienced diarrhea with duration greater than or equal to 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 (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 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 distensionTransaminases 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 fractureAdverse Reaction(Any Grade)Placebon=46LIVMARLIn=47Diarrhea9 (19.6%)27 (57.4%)Abdominal pain+ (15.2%)13 (27.7%)Transaminases increased (ALT or AST) 3 (6.5%)8 (17%)Hematochezia or rectal hemorrhage (2.2%)4 (8.5%)Bone Fractures+ 03 (6.4%)HepatotoxicityLIVMARLI treatment is associated with 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 ComplicationsIn 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 FractureIn 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.BleedingIn PFIC patients in Trial 2, treatment-emergent events of hematochezia (4 [8.5%] versus [2.2%]), decrease in hemoglobin greater than or equal to grams/dL from baseline (8 [17%] versus [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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhageGeneral disorders and administration site conditions: drug ineffectiveInjury, poisoning and procedural complications: off label useInvestigations: gamma-glutamyltransferase increasedNervous system disorders: intracranial hemorrhage.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Maralixibat is 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 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 decrease in serum bile acids [see Clinical Pharmacology (12.2)].. 12.2 Pharmacodynamics. ALGSIn 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 umol/L and mean (SD) serum bile acid level was 283 (210.6) umol/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.PFICIn 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 to 504 umol/L and mean (SD) serum bile acid level was 253 (136) umol/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 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.AbsorptionMaralixibat 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 single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following 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 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 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 FoodConcomitant administration of high-fat meal with 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)].DistributionMaralixibat shows high binding (91%) to human plasma proteins in vitro.EliminationFollowing single dose of 30 mg maralixibat oral solution in healthy adults, the mean half-life (t1/2) was 1.6 hours.MetabolismNo 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 [14C]maralixibat as an oral solution.ExcretionFecal excretion was found to be the major route of elimination. Following single dose of mg 14C-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 PopulationsPatients with Renal ImpairmentThe 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 StudiesEffect of Other Drugs on MaralixibatMaralixibat is not 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 DrugsIn 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 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 clinical study.. 12.5 Pharmacogenomics. PFIC is 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 (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 non-functional protein. PFIC3 is caused by variants in the ABCB4 gene, which encodes multidrug resistance protein (MDR3). PFIC4 is caused by variants in the tight junction protein 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 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 global consortium characterizing the natural history of severe BSEP deficiency.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oUse LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. (2.1)oUse LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. (2.1)oLIVMARLI 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 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 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 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 maximum daily dose of 38 mg per day for the oral solution and 40 mg per day for the tablets. (2.3)oSee full prescribing information for additional dosage details for LIVMARLI oral solution and tablet formulations. (2.2, 2.3). oUse LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. (2.1). oUse LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. (2.1). oLIVMARLI 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 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 maximum daily dose of 28.5 mg per day for the oral solution and 30 mg per day for the tablets. (2.2). The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before 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 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 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 maximum daily dose of 38 mg per day for the oral solution and 40 mg per day for the tablets. (2.3). The recommended dosage is 570 mcg/kg twice daily before 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 maximum daily dose of 38 mg per day for the oral solution and 40 mg per day for the tablets. (2.3). oSee full prescribing information for additional dosage details for LIVMARLI oral solution and tablet formulations. (2.2, 2.3). 2.1Important Administration Information. oUse LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS.oUse LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC.oThe 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)]. oLIVMARLI 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 patients weight and ability to swallow tablets [see Dosage and Administration (2.2 2.3)]. oUse LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS.. oUse LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC.. oThe 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)]. oLIVMARLI 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 patients weight and ability to swallow tablets [see Dosage and Administration (2.2 2.3)]. 2.2Recommended 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 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 for LIVMARLI Oral Solution and Table for LIVMARLI tablets.Table 1: 9.5 mg/mL LIVMARLI Oral Solution for Patients with ALGS: Volume per Dose (mL) by WeightPatient 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 60.10.27 to 90.150.310 to 120.20.4513 to 150.30.616 to 190.350.720 to 240.450.925 to 290.5130 to 340.61.2535 to 390.71.540 to 490.91.7550 to 5912.2560 to 691.252.570 or higher1.53Table 2: LIVMARLI Tablets for Patients with ALGS: Dosage by WeightSelect the appropriate product based on the patients weight and ability to swallow tablets.Patient Weight(kg)Days to 7(190 mcg/kg QD)Beginning Day 8(380 mcg/kg QD)Less than 25Use Oral SolutionUse Oral Solution25 to 3210 mg33 to 4315 mg44 to 6510 mg20 mg66 or higher15 mg30 mg. 2.3Recommended 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 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 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 for LIVMARLI oral solution and Table for LIVMARLI tablets.Table 3: 19 mg/mL LIVMARLI Oral Solution for Patients with PFIC: Volume per Dose (mL) by WeightPatient 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)50.10.10.156 to 70.10.150.28 0.10.20.2590.150.20.2510 to 120.150.250.313 to 150.20.30.416 to 190.250.40.520 to 240.30.50.625 to 290.40.60.830 to 340.450.70.935 to 390.60.8140 to 490.60.9150 to 590.81160 or higher0.911Table 4: LIVMARLI Tablets for Patients with PFIC: Dosage by WeightSelect the appropriate product based on the patients weight and ability to swallow tablets.Patient Weight (kg)285 mcg/kg BID428 mcg/kg BID570 mcg/kg BIDLess than 25Use Oral SolutionUse Oral SolutionUse Oral Solution25 to 3215 mg33 to 4310 mg15 mg20 mg44 or higher15 mg20 mg20 mg. 2.4Missed Dose. For once daily dosing: If 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 dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed.For twice daily dosing: If dose is missed, it should be taken as soon as possible within hours of the time it is usually taken, and the original dosing schedule should be resumed. If dose is missed by more than hours, the dose can be omitted and the original dosing schedule resumed.. 2.5Important Administration Instructions. Administer LIVMARLI oral solution and tablets 30 minutes before meal [see Clinical Pharmacology (12.3)].A calibrated measuring device (0.5 mL, mL or 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 30C (86F) and discard any remaining LIVMARLI oral solution after 100 days.. 2.6Dosage 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 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 patient experiences hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy).. 2.7Administration Modification for Drug Interaction Bile Acid Binding ResinsAdminister LIVMARLI at least hours before or hours after administering the bile acid binding resins [see Drug Interactions (7.1) when used concomitantly.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or their caregiver(s) to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Administration InstructionsAdvise patients or their caregivers(s) to:oTake LIVMARLI 30 minutes prior to meal once or twice daily as prescribed.oFor LIVMARLI oral solution, use calibrated measuring device (0.5 mL, mL or mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.2, 2.3, 2.5)].oTake LIVMARLI at least hours before or hours after taking bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].oStore the opened LIVMARLI oral solution bottle below 300C (860F). Discard any unused LIVMARLI 100 days after opening the oral solution bottle [see How Supplied/Storage and Handling (16)].HepatotoxicityAdvise patients or their caregiver(s) that liver tests should be obtained before starting LIVMARLI and periodically during LIVMARLI therapy. Inform patients or their caregiver(s) of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury. Instruct patients or their caregiver(s) to immediately report any signs or symptoms of severe liver injury to their healthcare provider [see Warnings and Precautions (5.1)]. Gastrointestinal Adverse ReactionsAdvise patients or their caregiver(s) to notify their healthcare provider if they experience new onset or worsening of gastrointestinal symptoms (abdominal pain, vomiting, bloody stool, and diarrhea) [see Warnings and Precautions (5.2)]. Fat Soluble Vitamin (FSV) DeficiencyAdvise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, will be obtained before starting treatment and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3) ]. Inform patients or their caregiver(s) that they may bleed more easily, may bleed longer, or have bone fracture. Advise patients or their caregiver(s) to call their healthcare provider for any signs or symptoms of bleeding or report any fractures. Rx onlyManufactured for:Mirum Pharmaceuticals, Inc.989 E. Hillsdale Blvd., Suite 300Foster City, CA 94404(C) 2025 Mirum Pharmaceuticals, Inc.LIVMARLI(R) is registered trademark of Mirum Pharmaceuticals, Inc.LB00203 LB00212. oTake LIVMARLI 30 minutes prior to meal once or twice daily as prescribed.. oFor LIVMARLI oral solution, use calibrated measuring device (0.5 mL, mL or mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.2, 2.3, 2.5)].. oTake LIVMARLI at least hours before or hours after taking bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].. oStore the opened LIVMARLI oral solution bottle below 300C (860F). Discard any unused LIVMARLI 100 days after opening the oral solution bottle [see How Supplied/Storage and Handling (16)].

PHARMACOKINETICS SECTION.

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 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.AbsorptionMaralixibat 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 single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following 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 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 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 FoodConcomitant administration of high-fat meal with 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)].DistributionMaralixibat shows high binding (91%) to human plasma proteins in vitro.EliminationFollowing single dose of 30 mg maralixibat oral solution in healthy adults, the mean half-life (t1/2) was 1.6 hours.MetabolismNo 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 [14C]maralixibat as an oral solution.ExcretionFecal excretion was found to be the major route of elimination. Following single dose of mg 14C-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 PopulationsPatients with Renal ImpairmentThe 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 StudiesEffect of Other Drugs on MaralixibatMaralixibat is not 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 DrugsIn 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 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 clinical study.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION LIVMARLI(R) (liv-MAR-lee) (maralixibat)oral solution and tablets, for oral use What is LIVMARLIoLIVMARLI is prescription medicine used to treat: ocholestatic pruritus (itch) in patients months of age and older with Alagille syndrome (ALGS).ocholestatic pruritus (itch) in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).oLIVMARLI is not for use in PFIC type patients who have severe defect in the bile salt export pump (BSEP) protein.oIt is not known if LIVMARLI is safe and effective in children with ALGS who are under months of age.oIt is not known if LIVMARLI is safe and effective in children with PFIC who are under 12 months of age. oIt is not known if LIVMARLI is safe and effective in adults 65 years of age and older.Before taking LIVMARLI, tell your healthcare provider about all of your medical conditions, including if you:oare pregnant or plan to become pregnant. It is not known if LIVMARLI will harm your unborn baby. Tell your healthcare provider right away if you think that you are pregnant. oare breastfeeding or plan to breastfeed. It is not known if LIVMARLI passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take LIVMARLI.Tell your healthcare provider about all medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. LIVMARLI may affect the way some other medicines work, and some other medicines may affect the way LIVMARLI works.How should you take LIVMARLI oLIVMARLI is available in oral solution and tablet.Read the Instructions for Use that comes with LIVMARLI for information about the right way to prepare and take LIVMARLI oral solution.oLIVMARLI oral solution comes in different strengths:oLIVMARLI oral solution 9.5 mg/mL for use in ALGSoLIVMARLI oral solution 19 mg/mL for use in PFICoBefore you take LIVMARLI oral solution for the first time, talk to your healthcare provider or pharmacist about how to measure the prescribed dose.oTake LIVMARLI exactly as your healthcare provider tells you to.oYour healthcare provider may start you on low dose of LIVMARLI and then increase the dose, especially if you have not taken LIVMARLI.oDo not change your dose of LIVMARLI unless your healthcare provider tells you to.oLIVMARLI is taken by mouth, or times each day (if times per day, take in the morning and evening), 30 minutes before meal. oIf you miss dose of LIVMARLI and you take LIVMARLI 1-time day: oIf it is 12 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.oIf it is more than 12 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time. oIf you miss dose of LIVMARLI and you take LIVMARLI 2-times day: oIf it is hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.oIf it is more than hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.oIf you take medicine that lowers cholesterol by binding bile acids, such as cholestyramine, colesevelam, or colestipol, take it at least hours before or hours after you take LIVMARLI. Ask your healthcare provider if you are not sure if you take these medicines.oIf you take too much LIVMARLI, call your healthcare provider or go to the nearest emergency room right away. oAfter opening the LIVMARLI oral solution bottle, store below 30C (86F). Throw away any remaining LIVMARLI oral solution 100 days after first opening the bottle.What are the possible side effects of LIVMARLI LIVMARLI can cause serious side effects, including:oLiver injury. Changes in certain liver tests are common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. These changes may be sign of liver injury and can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment with LIVMARLI to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including:onausea or vomitingoyour skin or the white part of your eye turns yellowodark or brown urineopain on the right side of your stomach (abdomen)ofullness, bloating, or fluid in your stomach area (ascites)oloss of appetite obleeding or bruising more easily than normal, including vomiting blood oStomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain during treatment. Diarrhea can also cause the loss of too much body fluid (severe dehydration). Your healthcare provider should check your stool for blood and monitor you for too much body fluid loss. Tell your healthcare provider right away if you have any new or worsening signs or symptoms of stomach and intestinal problems including:odiarrheaomore frequent bowel movements than usualostools that are black, tarry, sticky, or have blood or mucousosevere stomach-area pain or tendernessTell your healthcare provider if you have any signs and symptoms of loss of too much body fluid including:ovomitingodiarrheaourinating less often than usualoheadacheodizzinessoA condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat. FSV deficiency is common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. Your healthcare provider should do blood tests before starting and during treatment with LIVMARLI. Other common side effects of FSV deficiency reported during treatment with LIVMARLI were bone fractures and bleeding. Tell your healthcare provider if you have signs or symptoms of bleeding or any fractures.Your healthcare provider may change your dose, or temporarily or permanently stop treatment with LIVMARLI if you have certain side effects. These are not all of the possible side effects of LIVMARLI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LIVMARLIoStore unopened LIVMARLI oral solution and tablet bottles at room temperature between 68oF and 77oF (20oC and 25C).oAfter opening the LIVMARLI oral solution bottle, store below 30oC (86oF). Throw away any remaining LIVMARLI oral solution 100 days after first opening the bottle.Keep LIVMARLI and all medicines out of the reach of children.General information about the safe and effective use of LIVMARLI.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use LIVMARLI for condition for which it was not prescribed. Do not give LIVMARLI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LIVMARLI that is written for health professionals.What are the ingredients in LIVMARLIActive ingredients: maralixibat chloride. Oral Solution inactive ingredients: edetate disodium, grape flavor, propylene glycol, purified water, and sucralose. Tablet inactive ingredients crospovidone, glyceryl distearate, lactose monohydrate, microcrystalline cellulose, and silicon dioxide.Manufactured for: Mirum Pharmaceuticals, Inc., 989 E. Hillsdale Blvd., Suite 300, Foster City, CA 94404For more information, go to www.LIVMARLI.com or call 1-855-MRM-4YOULB00203 LB00212 This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: April 2025. oLIVMARLI is prescription medicine used to treat: ocholestatic pruritus (itch) in patients months of age and older with Alagille syndrome (ALGS).ocholestatic pruritus (itch) in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).. ocholestatic pruritus (itch) in patients months of age and older with Alagille syndrome (ALGS).. ocholestatic pruritus (itch) in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).. oLIVMARLI is not for use in PFIC type patients who have severe defect in the bile salt export pump (BSEP) protein.. oIt is not known if LIVMARLI is safe and effective in children with ALGS who are under months of age.. oIt is not known if LIVMARLI is safe and effective in children with PFIC who are under 12 months of age. oIt is not known if LIVMARLI is safe and effective in adults 65 years of age and older.. oare pregnant or plan to become pregnant. It is not known if LIVMARLI will harm your unborn baby. Tell your healthcare provider right away if you think that you are pregnant. oare breastfeeding or plan to breastfeed. It is not known if LIVMARLI passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take LIVMARLI.. oLIVMARLI is available in oral solution and tablet.. oLIVMARLI oral solution comes in different strengths:oLIVMARLI oral solution 9.5 mg/mL for use in ALGSoLIVMARLI oral solution 19 mg/mL for use in PFIC. oLIVMARLI oral solution 9.5 mg/mL for use in ALGS. oLIVMARLI oral solution 19 mg/mL for use in PFIC. oBefore you take LIVMARLI oral solution for the first time, talk to your healthcare provider or pharmacist about how to measure the prescribed dose.. oTake LIVMARLI exactly as your healthcare provider tells you to.. oYour healthcare provider may start you on low dose of LIVMARLI and then increase the dose, especially if you have not taken LIVMARLI.. oDo not change your dose of LIVMARLI unless your healthcare provider tells you to.. oLIVMARLI is taken by mouth, or times each day (if times per day, take in the morning and evening), 30 minutes before meal. oIf you miss dose of LIVMARLI and you take LIVMARLI 1-time day: oIf it is 12 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.oIf it is more than 12 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time. oIf it is 12 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.. oIf it is more than 12 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time. oIf you miss dose of LIVMARLI and you take LIVMARLI 2-times day: oIf it is hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.oIf it is more than hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.. oIf it is hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.. oIf it is more than hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.. oIf you take medicine that lowers cholesterol by binding bile acids, such as cholestyramine, colesevelam, or colestipol, take it at least hours before or hours after you take LIVMARLI. Ask your healthcare provider if you are not sure if you take these medicines.. oIf you take too much LIVMARLI, call your healthcare provider or go to the nearest emergency room right away. oAfter opening the LIVMARLI oral solution bottle, store below 30C (86F). Throw away any remaining LIVMARLI oral solution 100 days after first opening the bottle.. oLiver injury. Changes in certain liver tests are common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. These changes may be sign of liver injury and can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment with LIVMARLI to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including:onausea or vomitingoyour skin or the white part of your eye turns yellowodark or brown urineopain on the right side of your stomach (abdomen)ofullness, bloating, or fluid in your stomach area (ascites)oloss of appetite obleeding or bruising more easily than normal, including vomiting blood onausea or vomiting. oyour skin or the white part of your eye turns yellow. odark or brown urine. opain on the right side of your stomach (abdomen). ofullness, bloating, or fluid in your stomach area (ascites). oloss of appetite obleeding or bruising more easily than normal, including vomiting blood. oStomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain during treatment. Diarrhea can also cause the loss of too much body fluid (severe dehydration). Your healthcare provider should check your stool for blood and monitor you for too much body fluid loss. Tell your healthcare provider right away if you have any new or worsening signs or symptoms of stomach and intestinal problems including:. odiarrhea. omore frequent bowel movements than usual. ostools that are black, tarry, sticky, or have blood or mucous. osevere stomach-area pain or tenderness. ovomiting. odiarrhea. ourinating less often than usual. oheadache. odizziness. oA condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat. FSV deficiency is common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. Your healthcare provider should do blood tests before starting and during treatment with LIVMARLI. Other common side effects of FSV deficiency reported during treatment with LIVMARLI were bone fractures and bleeding. Tell your healthcare provider if you have signs or symptoms of bleeding or any fractures.. oStore unopened LIVMARLI oral solution and tablet bottles at room temperature between 68oF and 77oF (20oC and 25C).. oAfter opening the LIVMARLI oral solution bottle, store below 30oC (86oF). Throw away any remaining LIVMARLI oral solution 100 days after first opening the bottle.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryMaternal 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 ConsiderationsFetal/Neonatal Adverse ReactionsMaralixibat 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)].DataAnimal DataNo 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 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 SummaryLIVMARLI 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 mothers need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition.. 8.4 Pediatric Use. ALGSThe safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged months of age and older. Use of LIVMARLI in this population is supported by evidence from study of patients to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by 4 week placebo-controlled randomized withdrawal period and 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 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed 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 months of age.PFICThe 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 in patients 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 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHepatotoxicity: Obtain baseline liver tests and monitor patients frequently for the first to 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)oGastrointestinal Adverse Reactions: Consider reducing the dosage or interrupting LIVMARLI treatment if 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)oFat-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)oFracture: Consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.oBleeding: Interrupt treatment with LIVMARLI. Treatment can be restarted if the FSV deficiency is corrected and bleeding has resolved. oRisk of Propylene Glycol Toxicity (Pediatric Patients Less Than 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). oHepatotoxicity: Obtain baseline liver tests and monitor patients frequently for the first to 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). oGastrointestinal Adverse Reactions: Consider reducing the dosage or interrupting LIVMARLI treatment if 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). oFat-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)oFracture: Consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.oBleeding: Interrupt treatment with LIVMARLI. Treatment can be restarted if the FSV deficiency is corrected and bleeding has resolved. oFracture: Consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.. oBleeding: Interrupt treatment with LIVMARLI. Treatment can be restarted if the FSV deficiency is corrected and bleeding has resolved. oRisk of Propylene Glycol Toxicity (Pediatric Patients Less Than 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). 5.1Hepatotoxicity LIVMARLI treatment is associated with 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 to 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 patient experiences the following:opersistent or recurrent liver test abnormalities, oroupon rechallenge, signs and symptoms consistent with clinical hepatitis, oroa 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)].. opersistent or recurrent liver test abnormalities, or. oupon rechallenge, signs and symptoms consistent with clinical hepatitis, or. oa hepatic decompensation event.. 5.2Gastrointestinal 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 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.. 5.3Fat Soluble Vitamin (FSV) Deficiency. LIVMARLI may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and (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 (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 FractureTreatment-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.BleedingIf 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.. 5.4Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than Years of Age). LIVMARLI oral solution contains propylene glycol. Patients less than years of age are at highest risk for propylene glycol toxicity, and safe level for propylene glycol exposure with repeated administration has not been established for pediatric patients less than 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)].