Bylvay

Contraindications ( 4 ) 03/2025 Warnings and Precautions ( 5.1 ) 03/2025 Warnings and Precautions ( 5.3 ) 12/2025

1 INDICATIONS AND USAGE BYLVAY is an ileal bile acid transporter (IBAT) inhibitor indicated for: Progressive Familial Intrahepatic Cholestasis (PFIC) the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC). ( 1.1 ) Limitation of Use : BYLVAY is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump protein. ( 12.5 , 14.1 ) Alagille Syndrome (ALGS) the treatment of cholestatic pruritus in patients 12 months of age and older with Alagille syndrome (ALGS). ( 1.2 ) 1.1 Progressive Familial Intrahepatic Cholestasis (PFIC) BYLVAY is indicated for the treatment of pruritus in patients 3 months of age and older with PFIC. Limitations of Use BYLVAY is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump (BSEP) protein [see Clinical Pharmacology (12.5) and Clinical Studies (14.1) ]. 1.2 Alagille Syndrome (ALGS) BYLVAY is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with ALGS.

2 DOSAGE AND ADMINISTRATION Recommended Dosage PFIC: Patients 3 months and older: 40 mcg/kg taken orally once daily. ( 2.1 ) If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 mcg/kg increments up to 120 mcg/kg once daily, not to exceed a daily dosage of 6 mg/day. ( 2.1 ) ALGS: Patients 12 months and older: 120 mcg/kg taken orally once daily. ( 2.2 ) Preparation and Administration Instructions Administer BYLVAY in the morning with a meal. ( 2.4 ) Do not crush or chew capsules. ( 2.4 ) See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis (PFIC) in Patients Aged 3 Months and Older The recommended dosage of BYLVAY is 40 mcg/kg taken orally once daily in the morning with a meal. Table 1 below shows the recommended once daily dosage by body weight. If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 mcg/kg increments up to 120 mcg/kg once daily not to exceed a daily dosage of 6 mg/day. BYLVAY oral pellets are intended for use by patients weighing less than 19.5 kilograms. BYLVAY capsules are intended for use by patients weighing 19.5 kilograms or above. Table 1. Recommended Dosage for PFIC in Patients aged 3 months and older (40 mcg/kg/day) Body Weight (kg) Once Daily Dosage (mcg) 7.4 and below 200 7.5 to 12.4 400 12.5 to 17.4 600 17.5 to 25.4 800 25.5 to 35.4 1,200 35.5 to 45.4 1,600 45.5 to 55.4 2,000 55.5 and above 2,400 2.2 Recommended Dosage for Alagille Syndrome (ALGS) in Patients Aged 12 Months and Older The recommended dosage of BYLVAY is 120 mcg/kg taken orally once daily in the morning with a meal. Table 2 below shows the recommended once daily dosage by body weight. BYLVAY oral pellets are intended for use by patients weighing less than 19.5 kilograms. BYLVAY capsules are intended for use by patients weighing 19.5 kilograms or above. Table 2. Recommended Dosage for ALGS in Patients aged 12 months and older (120 mcg/kg/day) Body Weight (kg) Once Daily Dosage (mcg) 7.4 and below 600 7.5 to 12.4 1,200 12.5 to 17.4 1,800 17.5 to 25.4 2,400 25.5 to 35.4 3,600 35.5 to 45.4 4,800 45.5 to 55.4 6,000 55.5 and above 7,200 2.3 Dosage Modification for Management of Adverse Reactions Tolerability for Alagille Syndrome (ALGS) Dose reduction to 40 mcg/kg/day (Table 1) may be considered if tolerability issues occur in the absence of other causes. Once tolerability issues stabilize, increase to 120 mcg/kg/day. Liver Test Abnormalities Establish the baseline pattern of variability of liver tests prior to starting BYLVAY, 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 BYLVAY. Interrupt BYLVAY if new onset liver test abnormalities occur or symptoms consistent with clinical hepatitis are observed [see Warnings and Precautions (5.1) ]. Once the liver test abnormalities either return to baseline values or stabilize at a new baseline value, consider restarting BYLVAY at the recommended dosage [see Dosage and Administration (2.1 , 2.2) ] . Consider discontinuing BYLVAY permanently if liver test abnormalities recur. Discontinue BYLVAY permanently if a patient experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). 2.4 Preparation and Administration Instructions For patients taking bile acid binding resins, take BYLVAY at least 4 hours before or 4 hours after taking a bile acid binding resin [see Drug Interactions (7.1) ]. Do not crush or chew capsules. Oral Pellets: Mix the contents of the shell containing Oral Pellets into soft food or a liquid (as described below). Discard the emptied shells. Do not let your child swallow the unopened shells containing the Oral Pellets. Administration Instructions for pati …

3 DOSAGE FORMS AND STRENGTHS Oral Pellets: 200 mcg: capsule with ivory opaque cap and white opaque body; imprinted "A200" (black ink). 600 mcg: capsule with ivory opaque cap and body; imprinted "A600" (black ink). Capsules: 400 mcg: capsule with medium orange opaque cap and white opaque body; imprinted "A400" (black ink). 1200 mcg: capsule with medium orange opaque cap and body; imprinted "A1200" (black ink). Oral Pellets: 200 mcg, 600 mcg ( 3 ) Capsules: 400 mcg, 1200 mcg ( 3 )

4 CONTRAINDICATIONS IBAT inhibitors, including BYLVAY, are 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 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity [ see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precautions (5.2) ] Fat-Soluble Vitamin Deficiency [see Warnings and Precautions (5.3) ] PFIC: Most common adverse reactions (>2%) are liver test abnormalities, diarrhea, abdominal pain, vomiting, and fat-soluble vitamin deficiency. ( 6.1 ) ALGS: Most common adverse reactions (>5%) are diarrhea, abdominal pain, hematoma, and decreased weight. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. PFIC Clinical Studies Trial 1 is a randomized, double-blind, placebo-controlled, 24-week study of two dose levels of BYLVAY (40 mcg/kg and 120 mcg/kg) administered once daily [see Clinical Studies (14.1) ] . Sixty-two patients were randomized (1:1:1) to receive one of the following: BYLVAY 40 mcg/kg/day (n=23), BYLVAY 120 mcg/kg/day (n=19), or Placebo (n=20). Table 3 summarizes the frequency of adverse reactions reported in ≥2% and at a rate greater than placebo in patients treated with BYLVAY in Trial 1. The most common adverse reactions observed in Trial 1 included diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency. Table 3. Common Adverse Reactions Adverse reactions that occurred in ≥2% of BYLVAY-treated patients from a Clinical Study of BYLVAY in Patients with Progressive Familial Intrahepatic Cholestasis (Trial 1) Adverse Reaction Placebo N=20 n (%) BYLVAY 40 mcg/kg/day N=23 n (%) BYLVAY 120 mcg/kg/day N=19 n (%) Diarrhea 2 (10%) 9 (39%) 4 (21%) Transaminases increased (ALT, AST) 1 (5%) 3 (13%) 4 (21%) Vomiting 0 4 (17%) 3 (16%) Abdominal pain 0 3 (13%) 3 (16%) Blood bilirubin increased 2 (10%) 3 (13%) 2 (11%) Fat-soluble vitamin deficiency (A, D, E) 1 (5%) 0 3 (16%) Splenomegaly 0 0 2 (11%) Cholelithiasis 0 0 1 (5%) Dehydration 0 0 1 (5%) Fracture 0 1 (4%) 0 Trial 2 is an open-label, single-arm study in 116 patients with PFIC types 1, 2, 3, 4 and 6; four patients with benign recurrent intrahepatic cholestasis (BRIC) were also enrolled. BYLVAY 40 or 120 mcg/kg/day was administered once daily for 72 weeks, with the option to continue treatment beyond 72 weeks. Adverse reactions were similar to those observed in Trial 1. However, fractures were reported in a total of 6 patients (5%) in Trial 2. Adverse reactions observed in Trial 2 in addition to those described in Table 3 included increased INR (16%), epistaxis (9%), constipation (8%), coagulopathy (3%), headache (3%), nausea (3%), rash (3%), iron deficiency anemia (3%), gastroesophageal reflux disease (2%), prolonged prothrombin time (2%); and variceal hemorrhage, stoma hemorrhage, hematochezia, and rectal hemorrhage (<1% each). Adverse reactions leading to treatment discontinuation were increased bilirubin levels, diarrhea, progression of disease, increased INR, irritability, and decreased weight. There was a total of 19 (16%) patients who underwent surgical intervention in Trial 2, with one patient who had surgical biliary diversion (SBD) followed by liver transplant, 15 patients who underwent liver transplant alone, and three patients who underwent SBD alone. Overall, 11 of the 19 patients had these surgical interventions prior to Week 72. ALGS Clinical Studies Trial 3 is a randomized, double-blind, placebo-controlled, 24-week study of a single dose level of BYLVAY (120 mcg/kg) administered once daily [see Clinical Studies (14.2) ] . Fifty-two patients were randomized (2:1) to receive one of the following: BYLVAY 120 mcg/kg/day (n=35), or Placebo (n=1 …

7 DRUG INTERACTIONS 7.1 Bile Acid Binding Resins Administer bile acid binding resins (e.g., cholestyramine, colesevelam, or colestipol) at least 4 hours before or 4 hours after administration of BYLVAY [see Dosage and Administration (2.3) ] . Bile acid binding resins may bind odevixibat in the gut, which may reduce BYLVAY efficacy.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause cardiac malformations ( 8.1 ) 8.1 Pregnancy Risk Summary Limited human data on the use of BYLVAY in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes. Based on findings from animal reproduction studies, BYLVAY may cause cardiac malformations when a fetus is exposed during pregnancy. In pregnant rabbits treated orally with odevixibat during organogenesis, an increased incidence of malformations in fetal heart, great blood vessels, and other vascular sites occurred at all doses; maternal systemic exposure at the lowest dose was 2.1 times the maximum recommended dose (see Data ) . Odevixibat may inhibit the absorption of fat-soluble vitamins. FSV are essential for normal fetal growth and development. Monitor pregnant patients for FSV deficiency and supplement as needed. Increased supplementation of FSVs may be needed during pregnancy [see Warnings and Precautions (5.3) and Clinical Considerations ] . Consider the woman's need for BYLVAY, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal PFIC and ALGS. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. There is a pregnancy safety study that monitors pregnancy outcomes in women exposed to BYLVAY during pregnancy. Pregnant women exposed to BYLVAY, or their healthcare providers, should report BYLVAY exposure by calling 1-855-463-5127. Clinical Considerations Fetal/Neonatal Adverse Reactions Odevixibat may inhibit the absorption of fat-soluble vitamins (FSV). Monitor pregnant patients for FSV deficiency and supplement as needed. Increased supplementation of FSVs may be needed during pregnancy [see Warnings and Precautions (5.3) ]. Data Animal Data In an embryo-fetal development study, pregnant rabbits received oral doses of 10, 30, or 100 mg/kg/day during the period of organogenesis. Fetuses from all maternal groups treated with odevixibat showed an increase in cardiovascular malformations, which included 5-chambered heart, small ventricle, large atrium, ventricular septum defect, misshapen aortic valve, dilated aortic arch, right sided and retroesophageal aortic arch, fusion of aortic arch and pulmonary trunk, ductus arteriosus atresia, and absence of subclavian artery. These malformations occurred at 2.1 times the maximum recommended dose and higher, based on AUC (area under the plasma concentration-time curve). Odevixibat was shown to cross the placenta in pregnant rats. No adverse effects on embryo-fetal development were observed following oral administration of 100, 300, or 1,000 mg/kg/day in pregnant rats during organogenesis. An increase in skeletal variations (delayed/incomplete ossification and thick ribs) was observed at 1,000 mg/kg/day. Maternal systemic exposure to odevixibat at the maximum dose tested was 272 times the maximum recommended dose, based on AUC. No adverse effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with up to 1,000 mg/kg/day during organogenesis through lactation. The maternal AUC for odevixibat at 1,000 mg/kg/day was 434 times the maximum recommended dose, based on AUC. 8.2 Lactation Risk Summary Odevixibat has low absorption following oral administration, and exposure of the infant to BYLVAY through breast milk is not expected at the recommended doses [see Clinical Pharmacology (12.3) ]. There are no data on the presence of odevixibat in human milk, the effects on the breastfed infant, or the effects on milk production. BYLVAY may reduce absorption of fat-soluble vitamins [see Warning and Precautions (5.3) ] . Monitor FSV le …

12.1 Mechanism of Action Odevixibat 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 PFIC and ALGS; the pathophysiology of pruritus in patients with PFIC is not completely understood. Although the complete mechanism by which odevixibat improves pruritus in both PFIC and ALGS 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) ] .

11 DESCRIPTION The active ingredient in BYLVAY (odevixibat) capsules and BYLVAY (odevixibat) oral pellets, an ileal bile acid transporter (IBAT) inhibitor, is (2S)-2-{[(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,2,5-benzothiadiazepin-8yl]oxy}acetamido)-2-(4-hydroxyphenyl)acetly]amino}butanoic acid, which is formulated as the sesquihydrate having the following chemical structure: The molecular formula is C 37 H 48 N 4 O 8 S 2 × 1.5 H 2 O, with a molecular weight of 768.0 g/mol (anhydrous 740.9 g/mol). Odevixibat sesquihydrate is a white to off-white solid. Its solubility in aqueous solutions is pH-dependent and increases with increased pH. BYLVAY is available for oral administration as oral pellets containing odevixibat sesquihydrate equivalent to 200 mcg or 600 mcg of odevixibat, and as capsules containing odevixibat sesquihydrate equivalent to 400 mcg or 1200 mcg of odevixibat, and the following excipients: hypromellose and microcrystalline cellulose. The capsule shells for the oral pellets contain hypromellose, titanium dioxide and yellow iron oxide. The capsule shells for the capsules contain hypromellose, red iron oxide, titanium dioxide and yellow iron oxide. The imprinting ink contains ferrosoferric oxide/black iron oxide and shellac glaze. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING Oral Pellets 200 mcg Oral Pellets: supplied as Size 0 capsule with ivory opaque cap and white opaque body; imprinted "A200" (black ink). Supplied in bottles of 30 with child-resistant closure (NDC 15054-3301-1). 600 mcg Oral Pellets: supplied as Size 0 capsule with ivory opaque cap and body; imprinted "A600" (black ink). Supplied in bottles of 30 with child-resistant closure (NDC 15054-3303-1). Capsules 400 mcg Capsule: supplied as Size 3 capsule with medium orange opaque cap and white opaque body; imprinted "A400" (black ink). Supplied in bottles of 30 with child-resistant closure (NDC 15054-3302-1). 1,200 mcg Capsule: supplied as Size 3 capsule with medium orange opaque cap and body; imprinted "A1200" (black ink). Supplied in bottles of 30 with child-resistant closure (NDC 15054-3304-1). Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F) [See USP Controlled Room Temperature].