BYLVAY

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

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.

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 patients capable of swallowing soft food: Administer BYLVAY with the first morning meal. Place a small amount (up to 2 tablespoons [30 mL]) of soft food (apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding) in a bowl. Keep the soft food at, or cooler than, room temperature. Open the shell containing Oral Pellets and empty the contents into the bowl of soft food. Gently tap the Oral Pellet shell to ensure that all contents have been dispersed. If the dose requires more than one shell of Oral Pellets, repeat Step 3. Gently mix until well dispersed and administer the entire dose immediately. Follow the dose with breast milk, infant formula, or other age-appropriate liquid. Do not store the mixture for future use. For patients unable to swallow soft food, see the instructions below . Administration Instructions with liquids (Using an oral dosing syringe): Administer BYLVAY with the first morning meal. Open the shell containing Oral Pellets and empty the contents into a small mixing cup. Gently tap the shell containing Oral Pellets to ensure that all contents have been emptied into the mixing cup. If the dose requires more than one shell of Oral Pellets, repeat Step 2. Add 1 teaspoon (5 mL) of an age-appropriate liquid (for example, breast milk, infant formula, or water). Let the pellets sit in the liquid for approximately 5 minutes to allow complete wetting REMINDER: The Oral Pellets will not dissolve in the liquid. After 5 minutes, place the tip of the oral syringe completely into the mixing cup. Pull the plunger of the syringe up slowly to withdraw the liquid/pellet mixture into the syringe. Gently push the plunger down again to expel the liquid/pellet mixture back into the mixing cup. Do this 2 to 3 times to ensure complete mixing of the pellets into the liquid. Withdraw the entire contents into the oral syringe by pulling the plunger on the end of the syringe. Place the tip of the syringe into the front of the patient's mouth between the tongue and the side of the mouth, and then gently push the plunger down to squirt the liquid/pellet mixture between your child's tongue and the side of the mouth. Do not squirt liquid/pellet mixture in the back of the child's throat because this could cause gagging or choking. Do not administer via a bottle or "sippy cup" because the Oral Pellets will not pass through the opening. The oral pellets will not dissolve in liquid. Follow the dose with breast milk, infant formula, or other age-appropriate liquid. If any pellet/liquid mixture remains in the mixing cup, repeat Step 7 and Step 8 until the entire dose has been administered. Check the child's mouth to make sure all of the liquid/pellet mixture has been swallowed. Capsules: Administration Instructions: Take in the morning with a meal. Swallow the capsule whole with a glass of water. Alternatively, for patients unable to swallow the capsules whole, BYLVAY capsules may be opened, and sprinkled and mixed with a small amount of soft food, or mixed with an age-appropriate liquid. Follow directions above for oral pellets to prepare and administer such a mixture.

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 )

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=17). Table 4 summarizes the frequency of adverse reactions in patients with ALGS, reported in ≥5% and at a rate greater than placebo in patients treated with BYLVAY in Trial 3. No patients discontinued study treatment due to an adverse reaction. The most common adverse reactions observed in Trial 3 included diarrhea, abdominal pain, hematoma, and decreased weight. Table 4. Common Adverse Reactions Adverse reactions that occurred in ≥5% of BYLVAY-treated patients from a Clinical Study of BYLVAY in Patients with Alagille Syndrome (Trial 3) Adverse Reaction Placebo N=17 n (%) BYLVAY 120 mcg/kg/day N=35 n (%) Diarrhea 1 (6%) 10 (29%) Abdominal Pain 1 (6%) 5 (14%) Hematoma 0 3 (9%) Weight decreased 0 2 (6%) Trial 4 is an open-label, single-arm study in 50 pediatric patients with ALGS. BYLVAY 120 mcg/kg/day was administered once daily for 72 weeks, with the option to continue beyond 72 weeks. Adverse reactions observed in Trial 4 in addition to those described in Table 4 included FSV deficiency (vitamin D deficiency [14%], vitamin E deficiency [10%], vitamin K deficiency [6%]), ALT increased (6%), headache (6%), increased INR (6%), increased blood bilirubin (4%), increased AST (4%), coagulopathy (4%), fracture (4%); nausea, vomiting, hematemesis, hematochezia, epistaxis, and constipation (2% each). The most common reason for BYLVAY treatment discontinuation was increased bilirubin levels. One patient underwent liver transplant in Trial 4 prior to Week 72 with no patients underwent SBD. Hepatotoxicity BYLVAY treatment is associated with a potential for DILI. In the PFIC and ALGS trials, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Of the six patients who experienced DILI, two underwent liver transplant. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BYLVAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders : gastrointestinal hemorrhage, gingival hemorrhage, liver transplant Investigations : gamma-glutamyltransferase increased, hemoglobin decreased Nervous system disorders: extra-axial hemorrhage (subdural hemorrhage) Respiratory, thoracic, and mediastinal disorders: epistaxis

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.

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].