Bylvay Drug Information

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.

Alagille Syndrome (ALGS)

BYLVAY is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with ALGS.

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 . 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 . 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, vitamin E deficiency, vitamin K deficiency ), 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.

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

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 . Bile acid binding resins may bind odevixibat in the gut, which may reduce BYLVAY efficacy.

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 . 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. 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.

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) . 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) . 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.

inhibitors, including BYLVAY, are contraindicated in patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy) . Patients with prior or active hepatic decompensation events (e.g., variceal hemorrhage, ascites, hepatic encephalopathy).