Limitations of Use

• BYLVAY may not be effective 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 [see Clinical Pharmacology (12.5) and Clinical Studies (14)].

2.1 Recommended Dosage

• The recommended dosage of BYLVAY is 40 mcg/kg once daily in the morning with a meal.
• 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 total daily dose of 6 mg.

Table 1 below shows the recommended weight-based total daily dosage needed for the recommended dosage at 40 mcg/kg once daily.

• 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 40 mcg/kg/day

  Body Weight (kg)	Total Daily Dose (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	1200
  35.5 to 45.4	1600
  45.5 to 55.4	2000
  55.5 and above	2400

2.2 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:
    1. Administer BYLVAY with the first morning meal.
    2. 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.
    3. 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.
    4. If the dose requires more than one shell of Oral Pellets, repeat Step 2 and Step 3.
    5. Gently mix until well dispersed and administer the entire dose immediately.
    6. Follow the dose with breast milk, infant formula, or other age-appropriate liquid.
    7. Do not store the mixture for future use.
    8. For patients unable to swallow soft food, see the instructions below.
    Administration Instructions with liquids (Using an oral dosing syringe):
    1. Administer BYLVAY with the first morning meal.
    2. 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.
    3. Add 1 teaspoon (5 mL) of an age-appropriate liquid (for example, breast milk, infant formula, or water).
    4. If the dose requires more than one shell of Oral Pellets, repeat Step 2 and Step 3.
    5. 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.
    6. 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.
    7. Withdraw the entire contents into the oral syringe by pulling the plunger on the end of the syringe.
    8. 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.
    9. 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.
    10. Follow the dose with breast milk, infant formula, or other age-appropriate liquid.
    11. If any pellet/liquid mixture remains in the mixing cup, repeat Step 7 and Step 8 until the entire dose has been administered.
    12. Check the child's mouth to make sure all of the liquid/pellet mixture has been swallowed.

   

  Capsules:

   

  Administration Instructions:

  1. Take in the morning with a meal.
  2. Swallow the capsule whole with a glass of water.
  3. 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.

2.3 Dose Modification for Management of Adverse Events

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 lowest dose of 40 mcg/kg, and increase as tolerated if appropriate. 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).

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).

5.1 Liver Test Abnormalities

Patients enrolled in the trial had abnormal liver tests at baseline. In Trial 1, treatment-emergent elevations of liver tests or worsening of liver tests relative to baseline values were observed during the clinical trial. Most abnormalities included elevation in AST, ALT, or total and direct bilirubin (see Table 2). Treatment interruption days ranged from 3 days to 124 days; none of the patients in Trial 1 permanently discontinued treatment due to liver test abnormalities [see Adverse Reactions (6.1)].

Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation [see Dosage and Administration (2.3)].

BYLVAY was not evaluated in PFIC patients with cirrhosis. Closely monitor for liver test abnormalities; permanently discontinue BYLVAY if a patient progresses to portal hypertension or experiences a hepatic decompensation event.

5.2 Diarrhea

In Trial 1, diarrhea 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.

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 (FSV) Deficiency

Fat-soluble vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels). PFIC patients can have FSV deficiency at baseline. BYLVAY may affect absorption of fat-soluble vitamins. In Trial 1, 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 BYLVAY-treated 40 mcg/kg/day patients had new onset or worsening of existing FSV deficiency [see Adverse Reactions (6.1)].

Obtain serum FSV levels at baseline and monitor during treatment, along with any clinical manifestations. If FSV deficiency is diagnosed, supplement with FSV. Discontinue BYLVAY if FSV deficiency persists or worsens despite adequate FSV supplementation.

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.

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 clinical adverse events (AEs), regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with BYLVAY in Trial 1. Overall, about 85% of patients experienced AEs. The most common adverse reactions observed in Trial 1 included diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency.

Trial 2 is a 72-week, open-label, single-arm trial in PFIC type 1, 2, and 3 patients. Age of the enrolled patients ranged from 4 months to 25 years. BYLVAY 120 mcg/kg/day was administered once daily. A total of 79 PFIC patients have been enrolled, of which 56 patients were rolled over from Trial 1. In addition to patients rolled over from Trial 1, an additional 23 patients were enrolled to Trial 2. Treatment-emergent adverse events were similar as observed in Trial 1. The most common reason for BYLVAY treatment interruption was liver test abnormalities (increases in ALT, AST, direct and total bilirubin). Of the 12 patients who discontinued BYLVAY in Trial 2, one patient underwent biliary diversion surgery, and a second patient received liver transplantation; both underwent surgical intervention secondary to intolerable pruritus, unresponsive to BYLVAY treatment.

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

8.1 Pregnancy

8.2 Lactation

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 a 24-week, 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 72-week extension trial in PFIC patients (Trial 2) [see Adverse Reactions (6.1) and Clinical Studies (14)]. Results showed a greater improvement in pruritus in patients treated with BYLVAY compared with patients treated with placebo [see Clinical Studies (14)]. Common reported adverse reactions in BYLVAY-treated patients from Trials 1 and 2 were liver test abnormalities, gastrointestinal symptoms (abdominal pain, vomiting and diarrhea), and fat-soluble vitamin deficiency [see Adverse Reactions (6.1) and Warning and Precaution (5.1, 5.2, 5.3)].

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.

8.5 Geriatric Use

The safety and effectiveness of BYLVAY for the treatment of pruritus in PFIC in adult patients, including those 65 years of age and older, have not been established.

8.6 Hepatic Impairment

Patients with PFIC may have impaired hepatic function at baseline. The efficacy and safety in PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis have not been established [see Clinical Studies (14), Dosage and Administration (2.3), and Warning and Precautions (5.1)].

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 the pathophysiology of pruritus in patients with PFIC is not completely understood. Although the complete mechanism by which odevixibat improves pruritus in PFIC 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)].

12.2 Pharmacodynamics

Odevixibat reduces serum bile acids in patients with PFIC. In Trial 1, a 24-week, randomized, double-blind, placebo-controlled trial conducted in 62 patients with a confirmed diagnosis of PFIC type 1 or type 2, the majority of patients (88.7%) had elevated serum bile acids above 100 µmol/L at baseline [see Clinical Studies (14)]. Serum bile acids concentrations were reduced from baseline within 4-8 weeks of odevixibat treatment compared to placebo treatment. The decreased concentrations of serum bile acids fluctuated over time but generally were maintained during the treatment over 24 weeks. The extent of decrease in serum bile acids was similar between 40 and 120 mcg/kg.

12.3 Pharmacokinetics

In pediatric patients with PFIC, 6 months to 17 years of age who received BYLVAY 40 mcg/kg or 120 mcg/kg once daily with food in the morning, the measurable odevixibat concentrations ranged from 0.06 to 0.72 ng/mL, and odevixibat concentrations were below the limit of quantification (0.05 ng/mL) in the majority of plasma samples.

Following single and repeated oral administration of odevixibat from 0.1 to 3 mg in healthy adults, plasma concentrations of odevixibat were mostly below the limit of quantification (0.05 ng/mL); therefore, AUC and peak plasma concentration (Cmax) could not be calculated.

Following a single administration of odevixibat 7.2 mg in healthy adults, the mean (%CV) Cmax and AUC0-24h were 0.47 ng/mL (34.8) and 2.19 ng*h/mL (36.2), respectively. No accumulation of odevixibat was observed following once-daily dosing.

12.5 Pharmacogenomics

PFIC is a heterogenous disease caused by homozygous or compound heterozygous variants, with different PFIC subtypes occurring in the general population. PFIC2 is the most common subtype accounting for 37-90% of PFIC patients. PFIC1 is caused by variants in the ATP8B1 gene, which encodes the Familial Intrahepatic Cholestasis 1 (FIC1) protein, while PFIC2 results from variants in the ABCB11 gene, which encodes the Bile Salt Export Pump (BSEP) protein. PFIC2 patients are further categorized into BSEP subgroups based on their specific variants. The BSEP-1 subgroup includes patients with at least one p.D482G (c.1445A>G) or p.E297G (c.890A>G) variant, BSEP-2 includes patients with at least one missense variant other than p.D482G or p.E297G (non BSEP-1), and BSEP-3 includes patients with variants that are predicted to encode a non-functional protein. No BSEP-3 patients were studied in clinical Trial 1 (NCT03566238). The frequencies of BSEP-1, BSEP-2, and BSEP-3 subgroups within PFIC2 patients are approximately 27.3%, 51.5%, and 21.2%, respectively, based on data from a global consortium characterizing the natural history of severe BSEP deficiency.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 74528-020-01).

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 74528-060-01).

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 74528-040-01).

1200 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 74528-120-01).

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].

Risks

• Abdominal pain, vomiting, diarrhea, and dehydration have been reported with the use of BYLVAY. Advise patients to contact their healthcare provider if they experience new onset or worsening of diarrhea.
• Elevations in liver tests (for example, AST, ALT, TB) have been observed with use of BYLVAY. Advise patients that their healthcare provider will obtain liver tests before starting BYLVAY and periodically during treatment with BYLVAY. Advise patients to report any symptoms of liver problems (for example, nausea, vomiting, skin or the whites of eyes turn yellow, dark or brown urine, pain on the right side of the abdomen, loss of appetite).
• BYLVAY may impair absorption of fat-soluble vitamins (FSV), which include vitamins A, D, E and K (vitamin K is assessed by measuring INR). Advise patients that their healthcare provider will obtain serum levels of vitamins A, D, E, and INR (for vitamin K) at baseline and periodically during treatment to assess for worsening of FSV deficiency.

Administration

• Do not swallow the 200 mcg or 600 mcg capsule(s) containing Oral Pellets whole. These are intended to be opened and the contents mixed into soft food or liquids. Take BYLVAY in the morning with a meal.
• Follow stepwise administration Instructions [see Dosage and Administration (2.2)] for Oral Pellets and Capsules for patients unable to swallow the capsules whole.
• 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)]