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.

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 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.

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, AST, TB, DB and International Normalized Ratio ) during treatment with BYLVAY. Interrupt BYLVAY if new onset liver test abnormalities occur or symptoms consistent with clinical hepatitis are observed. Once the liver test abnormalities either return to baseline values or stabilize at a new baseline value, consider restarting BYLVAY at the recommended dosage.

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).

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. 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 ) 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.

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. 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.

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) 0 Trial 2 is an open-label, single-arm study in 116 patients with PFIC types four patients with benign recurrent intrahepatic cholestasis (BRIC) were also enrolled. 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 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). 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) 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. 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 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.

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.

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).

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