Odevixibat

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.

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 )

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 )

Hepatoxicity : 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 BYLVAY. Monitor patients with compensated cirrhosis or portal hypertension more frequently. Permanently discontinue BYLVAY if hepatic decompensation occurs. ( 2.3 , 5.1 ) Diarrhea : Treat dehydration. Treatment interruption or discontinuation may be required for persistent diarrhea. ( 5.2 ) Fat-Soluble Vitamin (FSV) Deficiency : Obtain baseline levels and monitor during treatment. Supplement with FSV if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, consider discontinuing BYLVAY treatment. Fracture: Consider interrupting BYLVAY treatment. Supplement with FSV if indicated. Bleeding: Interrupt treatment with BYLVAY. Optimize treatment of FSV deficiency and consider restarting BYLVAY once the patient is clinically stable. ( 5.3 )

5.1 Hepatoxicity BYLVAY treatment is associated with a potential for drug-induced liver injury (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. 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 BYLVAY. Monitor for elevation 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 BYLVAY 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 BYLVAY have not been established in patients with decompensated cirrhosis. Monitor patients with compensated cirrhosis or portal hypertension more frequently and discontinue BYLVAY if hepatic decompensation occurs. IBAT inhibitors, including BYLVAY, are contraindicated in patients with prior or active hepatic decompensation events [see Contraindications (4) ] .

5.2 Diarrhea In Trial 1, diarrhea in PFIC patients was reported in 2 (10%) placebo-treated patients, 9 (39%) BYLVAY-treated 40 mcg/kg/day patients and 4 (21%) BYLVAY-treated 120 mcg/kg/day patients. Treatment interruption due to diarrhea occurred in 2 patients with 3 events during treatment with BYLVAY 120 mcg/kg/day. Treatment interruption due to diarrhea ranged between 3 to 7 days [see Adverse Reactions (6.1) ] . One patient treated with BYLVAY 120 mcg/kg/day withdrew from Trial 1 due to persistent diarrhea. In Trial 3, diarrhea in ALGS patients was reported in 1 placebo-treated patient (6%) and in 10 (29%) BYLVAY-treated patients [see Adverse Reactions (6.1) ] . No patients interrupted or permanently discontinued BYLVAY due to diarrhea. If diarrhea occurs, monitor for dehydration and treat promptly. Interrupt BYLVAY dosing if a patient experiences persistent diarrhea. Restart BYLVAY at 40 mcg/kg/day when diarrhea resolves, and increase the dose as tolerated if appropriate. If diarrhea persists and no alternate etiology is identified, stop BYLVAY treatment.

5.3 Fat-Soluble Vitamin Deficiency BYLVAY may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamin A, D, E, and K (measured using INR levels). PFIC and ALGS patients can have FSV deficiency at baseline and are frequently supplemented with FSV. In Trial 1 in PFIC patients, new onset or worsening of existing FSV deficiency was reported in 1 (5%) placebo-treated patient, and 3 (16%) BYLVAY-treated 120 mcg/kg/day patients; none of the patients treated with BYLVAY dosage 40 mcg/kg/day had new onset or worsening of existing FSV deficiency. In Trial 3 in ALGS patients, new or worsening of existing FSV deficiency was reported in 3 (17.6%) placebo- treated patients and 3 (8.6%) BYLVAY-treated patients [see Adverse Reactions (6.1) ]. Obtain serum FSV levels at baseline and monitor during treatment, along with any clinical manifestations of FSV deficiency. If FSV deficiency is diagnosed, supplement with FSV. If FSV deficiency persists or worsens despite adequate FSV supplementation, consider permanent discontinuation of BYLVAY depending on the benefit and risk balance. If complications of FSV deficiency occur, consider interrupting BYLVAY treatment and reassess to ensure adequate supplementation with FSV. Consider restarting BYLVAY once the patient is clinically stable. Bone Fracture Fracture events have been observed with BYLVAY-treated patients in two open-label postmarketing studies (5% in PFIC patients and 4% in ALGS patients) [see Adverse Reactions (6) ] . If fracture occurs, consider interrupting BYLVAY treatment and supplement with FSV if indicated. Bleeding Interrupt treatment with BYLVAY if bleeding occurs. Optimize treatment of FSV deficiency and consider restarting BYLVAY once the patient is clinically stable.

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.

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 levels and increase FSV intake, if FSV deficiency is observed during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BYLVAY and any potential adverse effects on the breastfed child from BYLVAY or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of BYLVAY have been established in pediatric patients 3 months to 17 years of age for the treatment of pruritus in PFIC. Use of BYLVAY in this age group is supported by evidence from one randomized, double-blind, placebo-controlled trial conducted in 62 patients with a confirmed diagnosis of PFIC type 1 or type 2 (Trial 1), and an open-label extension trial in PFIC patients (Trial 2) [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . The safety and effectiveness of BYLVAY for the treatment of pruritus in PFIC in pediatric patients less than 3 months of age have not been established. The safety and effectiveness of BYLVAY have been established in pediatric patients 12 months to 17 years of age for the treatment of pruritus in ALGS. Use of BYLVAY in this age group is supported by evidence from one randomized, double-blind, placebo-controlled trial conducted in 52 patients with a confirmed diagnosis of ALGS (Trial 3) and one open-label extension trial in ALGS patients (Trial 4) [see Adverse Reactions (6.1) and Clinical Studies (14.2) ] . The safety and effectiveness of BYLVAY for the treatment of pruritus in ALGS in pediatric patients less than 12 months of age have not been established.

8.5 Geriatric Use PFIC and ALGS are largely diseases of pediatric and young adult patients. Clinical studies in BYLVAY did not include patients 65 years of age and older.

8.6 Hepatic Impairment Patients with PFIC and ALGS may have impaired hepatic function. The efficacy and safety of BYLVAY in PFIC and ALGS patients with clinically significant portal hypertension, and in patients with decompensated cirrhosis have not been established [see Dosage and Administration (2.3) , Contraindications (4) , Warning and Precautions (5.1) , and Clinical Studies (14) ].

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) ] .