maralixibat 30 MG Oral Tablet [Livmarli]

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

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

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) ].

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

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) ] .