Posology : מינונים

4.2   Posology and method of administration
Treatment must be initiated and supervised by physicians experienced in the management of PFIC.

Posology

Recommended Dosage for Progressive Familial Intrahepatic Cholestasis (PFIC) in Patients Aged 6 Months or Older

The recommended dose of odevixibat is 40 mcg/kg administered orally once daily in the morning.
Odevixibat can be taken with or without food.

Table 1 shows the strength and number of capsules that should be administered daily based on body weight to approximate a 40 mcg/kg/day dose.

Table 1: Number of Bylvay capsules needed to achieve the nominal dose of 40 mcg/kg/day Body weight (kg)       Number of 200 mcg capsules           Number of 400 mcg capsules 4 to < 7.5                      1                 or               N/A
7.5 to < 12.5                     2                 or                 1 12.5 to < 17.5                     3                 or               N/A 17.5 to < 25.5                     4                 or                 2 25.5 to < 35.5                     6                 or                 3
35.5 to < 45.5                     8                 or                 4 45.5 to < 55.5                    10                 or                 5
≥ 55.5                       12                 or                 6 Capsule strength/number in bold is recommended based on predicted ease of administration.

Dose escalation
Improvement in pruritus and reduction of serum bile acid levels may occur gradually in some patients after initiating odevixibat therapy. If an adequate clinical response has not been achieved after 3 months of continuous therapy, the dose may be increased to 120 mcg/kg/day (see section 4.4.).

Table 2 shows the strength and number of capsules that should be administered daily based on body weight to approximate a 120 mcg/kg/day dose, with a maximum daily dose of 7,200 mcg per day.

Table 2: Number of Bylvay capsules needed to achieve the nominal dose of 120 mcg/kg/day Body weight (kg)       Number of 600 mcg capsules               Number of 1,200 mcg capsules
4 to < 7.5                      1                 or                N/A
7.5 to < 12.5                     2                 or                 1 12.5 to < 17.5                     3                 or                N/A 17.5 to < 25.5                     4                 or                 2 25.5 to < 35.5                     6                 or                 3
35.5 to < 45.5                     8                 or                 4 45.5 to < 55.5                    10                 or                 5
≥ 55.5                              12                    or                    6 Capsule strength/number in bold is recommended based on predicted ease of administration.

Alternative treatment should be considered in patients for whom no treatment benefit can be established following 6 months of continuous daily treatment with odevixibat.

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 3 below shows the recommended once daily dosage by body weight.
Table 3. Recommended Dosage for ALGS in Patients aged 12 months and older (120 mcg/kg/day)

Body Weight (kg)                 Once Daily Dosage (mcg)
7.4 and below                             600
7.5 to 12.4                            1,200
12.5 to 17.4                            1,800
17.5 to 25.4                            2,400
25.5 to 35.4                            3,600
35.5 to 45.4                            4,800
45.5 to 55.4                            6,000
55.5 and above                            7,200

Dosage Modification for Management of Adverse Reactions
Tolerability for Alagille Syndrome (ALGS)
Dose reduction to 40 mcg/kg/day 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 [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 section 4.4].

Once the liver test abnormalities either return to baseline values or stabilize at a new baseline value, consider restarting BYLVAY at the recommended dosage [see section 4.2]. 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).

Missed doses
If a dose of odevixibat is missed, the patient should take the forgotten dose as soon as possible without exceeding one dose per day.

Special populations
Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment.
There are no available clinical data for the use of odevixibat patients with moderate or severe renal impairment or end-stage renal disease (ESRD) requiring haemodialysis (see section 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild or moderate hepatic impairment (see sections 5.1 and 5.2).

No data are available for PFIC patients with severe hepatic impairment (Child Pugh C). Additional monitoring for adverse reactions may be warranted in these patients when odevixibat is administered (see section 4.4).

Paediatric population
The safety and efficacy of odevixibat for the treatment of PFIC in children aged less than 6 months has not been established. No data are available.

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 sections 4.8 and 5.1].

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.

Method of administration

Bylvay is for oral use. To be taken with or without food in the morning (see section 5.2).
The larger 200 mcg and 600 mcg capsules are intended to be opened and sprinkled on food but may be swallowed whole.
The smaller 400 mcg and 1,200 mcg capsules are intended to be swallowed whole but may be opened and sprinkled on food.
If the capsule is to be swallowed whole, the patient should be instructed to take it with a glass of water in the morning.

For capsules to be opened, the patient should be instructed to:
•     place a small quantity (30 mL/2 tablespoons) of soft food (yoghurt, apple sauce, oatmeal porridge, banana puree, carrot puree, chocolate-flavoured pudding or rice pudding) in a bowl.
The food should be at or below room temperature.
•     hold the capsule horizontally at both ends, twist in opposite directions and pull apart to empty the pellets into the bowl of soft food. The capsule should be gently tapped to ensure that all pellets will come out.
•     repeat the previous step if the dose requires more than one capsule.
•     gently mix the pellets with a spoon into the soft food.
•     administer the entire dose immediately after mixing. Do not store the mixture for future use.
•     drink a glass of water following the dose.
•     dispose all empty capsule shells.