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.

1.2 Alagille Syndrome (ALGS)

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

2.1 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis (PFIC) in Patients Aged 3 Months and Older

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.

2.3 Dosage Modification for Management of Adverse Reactions

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:
    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 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. If the dose requires more than one shell of Oral Pellets, repeat Step 2.
    4. Add 1 teaspoon (5 mL) of an age-appropriate liquid (for example, breast milk, infant formula, or water).
    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.

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 PFIC trial had abnormal liver tests at baseline. In Trial 1 in PFIC patients, 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 3). 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)].

Patients enrolled in the ALGS trial had abnormal liver tests at baseline. In Trial 3 in ALGS patients, treatment-emergent elevations or worsening in liver tests relative to baseline values were observed during the trial. Most abnormalities included elevation in ALT or AST (see Table 4). One patient interrupted treatment for 40 days; none of the patients in Trial 3 permanently discontinued treatment due to liver test abnormalities.

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 or ALGS 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 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 (FSV) Deficiency

Fat-soluble vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels). PFIC and ALGS patients can have FSV deficiency at baseline, as part of their disease. 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. In Trial 3, 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. 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.

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.

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 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)].

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)].

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 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 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)].

12.2 Pharmacodynamics

Odevixibat reduces serum bile acids in patients with PFIC and ALGS.

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 mcmol/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.

Trial 3 is a 24-week, randomized, double-blind, placebo-controlled trial conducted in 52 patients with a confirmed diagnosis of ALGS who were administered treatment with BYLVAY 120 mcg/kg once daily [see Clinical Studies (14)]. At baseline, serum bile acids were variable ranging from 93 to 510 mcmol/L. Serum bile acid concentrations were reduced from baseline as early as Week 4 of odevixibat treatment and the reduction was generally maintained during treatment over 24 weeks.

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.

In pediatric patients with ALGS who received BYLVAY 120 mcg/kg once daily with food in the morning, the measurable odevixibat concentrations ranged from 0.05 to 3.4 ng/mL.

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 aminophospholipid flippase (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 prevalence of BSEP-1, BSEP-2, and BSEP-3 subgroups 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

14.1 PFIC

The efficacy of BYLVAY was evaluated in Trial 1 (NCT03566238), a 24-week, randomized, double-blind, placebo-controlled trial. Trial 1 was conducted in 62 pediatric patients, aged 6 months to 17 years, with a confirmed molecular diagnosis of PFIC type 1 or type 2, and presence of pruritus at baseline. Patients with variants in the ABCB11 gene that predict non-function or complete absence of the bile salt export pump (BSEP) protein, who had experienced prior hepatic decompensation events, who had other concomitant liver disease, whose INR was greater than 1.4, whose ALT or total bilirubin was greater than 10-times the upper limit of normal (ULN), or who had received a liver transplant were excluded in Trial 1.

Patients were randomized to placebo (n=20), 40 mcg/kg (n=23), or 120 mcg/kg (n=19). Study drug was administered once daily with a meal in the morning. In patients weighing less than 19.5 kg or patients who could not swallow the whole capsule, study drug was sprinkled on soft food and then administered orally.

Median age (range) of the patients in Trial 1 was 3.2 (0.5 to 15.9) years; 3 patients were older than 12 years of age. Of the 62 patients, 50% were male and 84% were white; 27% had PFIC type 1, and 73% had PFIC type 2. The mean (standard error [SE]) scratching score in the 2 weeks prior to baseline was 2.9 (0.08). Baseline mean (SE) eGFR was 164 (30.6) mL/min/1.73 m2. Baseline median (range) ALT, AST, and total bilirubin were 65 (16-798) U/L, 83.5 (32-405) U/L, and 2.2 (0.2-18.6) mg/dL, respectively.

In Trial 1, a total of 13 patients discontinued from trial prematurely either due to no improvement in pruritus (n=11) or due to adverse reactions (n=2); 5/20 (25%) patients discontinued from the placebo arm and 8/42 (19%) patients discontinued from the BYLVAY arms. A total of 11 of the 13 patients rolled over to Trial 2 to receive BYLVAY 120 mcg/kg/day. One patient treated with BYLVAY 120 mcg/kg/day withdrew from the trial due to a treatment-emergent adverse reaction of diarrhea [see Adverse Reactions (6)].

Given the patients' young age, a single-item observer-reported outcome (ObsRO) was used to measure patients' scratching severity as observed by their caregiver twice daily (once in the morning and once in the evening). Scratching severity was assessed on a 5-point ordinal response scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). Patients were included in Trial 1 if their average scratching score was greater than or equal to 2 (medium scratching) in the 2 weeks prior to baseline.

Table 7 presents the results of the comparison between BYLVAY and placebo on the mean of patients' percentage of ObsRO assessments over the 24-week treatment period that were scored as 0 (no scratching) or 1 (a little scratching). Patients treated with BYLVAY demonstrated greater improvement in pruritus compared with placebo. Figure 1 displays the mean of patients' worst weekly average scratching scores in each treatment group for each month, where the weekly average utilized the worst score from each day (morning or evening score).

14.2 ALGS

The efficacy of BYLVAY was evaluated in Trial 3 (NCT04674761), a 24-week, randomized, double-blind, placebo-controlled trial. Trial 3 was conducted in 52 pediatric patients, aged 6 months to 15 years, with a confirmed diagnosis of ALGS and presence of pruritus at baseline. Patients who had decompensated liver disease, who had other concomitant liver disease, whose INR was greater than 1.4, whose ALT was greater than 10-times the upper limit of normal (ULN) at screening, whose total bilirubin was greater than 15-times the ULN at screening, or who had received a liver transplant were excluded from Trial 3.

Patients were randomized to placebo (n=17) or 120 mcg/kg (n=35). Study drug was administered once daily with a meal in the morning. In patients weighing less than 19.5 kg or patients who could not swallow the whole capsule, study drug was sprinkled on soft food and then administered orally.

Median age (range) of the patients in Trial 3 was 6.1 (1.7 to 15.5) years in the BYLVAY group and 4.2 (0.5 to 14.3) years in the placebo group; 5 patients were older than 12 years of age. Of the 52 patients, 52% were male and 83% were white; 92% of patients had the JAG1 mutation and 8% had the NOTCH2 mutation. The mean (standard deviation [SD]) scratching score in the 2 weeks prior to baseline was 2.9 (0.6). Baseline mean (SD) eGFR was 159 (51.4) mL/min/1.73 m2. Baseline median (range) ALT, AST, and total bilirubin were 152 (39-403) U/L, 135 (57-427) U/L, and 2.0 (0.4-11.4) mg/dL, respectively.

Given the patients' young ages, a single-item observer-reported outcome (ObsRO) was used to measure patients' scratching severity as observed by their caregiver twice daily (once in the morning and once in the evening). Scratching severity was assessed on a 5-point ordinal response scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). Patients were included in Trial 3 if the average scratching score was greater than or equal to 2 (medium scratching) in the 14 days prior to baseline.

Table 8 presents the results of the comparison between BYLVAY and placebo on the change from baseline in average scratching score based on ObsRO assessments to Month 6 (Weeks 21 to 24). The average scratching score for each patient for each month post-baseline was calculated by: (Step 1) averaging the morning scores and averaging the evening scores within a week; (Step 2) averaging the morning and evening weekly scores to yield a single weekly score; and finally (Step 3) averaging the 4 weekly scores within the month. The baseline average scratching score for each patient was calculated by averaging the weekly scores obtained in Step 2 across the 2 weeks prior to randomization and initiation of blinded treatment. Patients treated with BYLVAY demonstrated greater improvement in pruritus compared with placebo. Figure 2 displays the means (95% confidence interval) of patients' average scratching scores in each treatment group for each month.

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).

1,200 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].

Administration Instructions

Advise patients or their caregivers(s) to:

• Take BYLVAY in the morning with a meal. 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 [see Dosage and Administration (2.1, 2.2, 2.4)].
• Follow stepwise administration Instructions [see Dosage and Administration (2.4)] for Oral Pellets and Capsules for patients unable to swallow the capsules whole.
• Take BYLVAY at least 4 hours before or 4 hours after taking a bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].

Liver Test Abnormalities

Advise patients or their caregiver(s) that liver tests should be obtained before starting BYLVAY and periodically during BYLVAY therapy, due to the risk of elevation in liver tests and development of liver-related adverse reactions [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Diarrhea

Advise patients or their caregiver(s) to notify their healthcare provider if they experience new onset or worsening of diarrhea [see Warnings and Precautions (5.2)].

Fat Soluble Vitamin (FSV) Deficiency

Advise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)].

Pregnancy

Advise patients or their caregiver(s) that there is a pregnancy safety study that collects pregnancy outcome data in women taking BYLVAY during pregnancy. Pregnant women exposed to BYLVAY, or their healthcare providers, should report BYLVAY exposure by calling 1-855-252-4736 [see Use in Specific Populations (8.1)].