4.1. Therapeutic indications

Bylvay is indicated for:

- treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older (see sections 4.4 and 5.1).treatment of cholestatic pruritus in Alagille syndrome (ALGS) in patients aged 6 months or older (see section 4.4 and 5.1).

4.2. Posology and method of administration

Treatment must be initiated and supervised by physicians experienced in the management of PFIC or ALGS. Table 1 shows the daily dose that should be administered based on body weight to approximate 40 mcg/kg/day for PFIC and 120 mcg/kg/day for ALGS.

PFIC

Posology

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

Dose escalation

In patients with PFIC, 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.).

ALGS

Posology

The recommended dose of odevixibat for treatment in AGLS is 120 mcg/kg administered orally once daily in the morning.

Dose reduction

In patients with ALGS, dose reduction to 40 mcg/kg/day may be considered if tolerability issues occur in the absence of other causes. Once tolerability issues stabilise, increase to 120 mcg/kg/day.

All available capsule strengths are interchangeable and may be swallowed whole or opened and sprinkled. The strength chosen to support total daily dose should be based on predicted ease of administration for each patient e.g. total numbers of capsules, size of capsules, ability to swallow whole capsules (Table 1).

Table 1: Recommended dosage

Body weight (kg)

Total daily dose (mcg) (for nominal dose of 40 mcg/kg/day)

Total daily dose (mcg) (for nominal dose of 120 mcg/kg/day)

4 to < 7.4

200

600

7.5 to < 12.4

400

1200

12.5 to < 17.4

600

1800

17.5 to < 25.4

800

2400

25.5 to < 35.4

1200

3600

35.5 to < 45.4

1600

4800

45.5 to < 55.4

2000

6000

≥ 55.5

2400

7200

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

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

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). However, due to minimal plasma concentrations and negligible renal excretion, no dose adjustment is required for patients with renal impairment.

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 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).

Elderly

The safety and efficacy of odevixibat in adult patients, including those 65 years of age and older have not been established.

Paediatric population

The safety and efficacy of odevixibat in patient less than 6 months has 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 in a liquid 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 or in a liquid.

If the capsule is to be swallowed whole, the patient should be instructed to take it with a glass of water in the morning.

Administration in soft foods

For capsules to be opened and sprinkled on soft food, 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 of all empty capsule shells.

Administration in liquids (requires use of an oral syringe)

For capsules to be opened and sprinkled in a liquid, the caregiver should be instructed to:

• hold the capsule horizontally at both ends, twist in opposite directions and pull apart to empty the pellets into a small mixing cup. 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.

• 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 (pellets will not dissolve).

• 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. Repeat this 2 to 3 times to ensure complete mixing of the pellets into the liquid (pellets will not dissolve).

• withdraw the entire contents into the syringe by pulling the plunger on the end of the syringe.

• place the tip of the syringe into the front of the child'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 the child's tongue and the side of the mouth. Do not squirt liquid/pellet in the back of the child's throat because this could cause gagging or choking.

• if any pellet/liquid mixture remains in the mixing cup, repeat the previous step until the entire dose has been administered. The mixture is not to be stored for future use.

• follow the dose with breast milk, infant formula or other age-appropriate liquid.

• dispose of all empty capsule shells.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

The mechanism of action of odevixibat requires that the enterohepatic circulation of bile acids and bile salt transport into biliary canaliculi is preserved. Conditions, medications or surgical procedures that impair either gastrointestinal motility, or enterohepatic circulation of bile acids, including bile salt transport to biliary canaliculi have the potential to reduce the efficacy of odevixibat. For this reason, e.g. patients with PFIC2 who have a complete absence or lack of function of Bile Salt Export Pump (BSEP) protein (i.e. patients with BSEP3 subtype of PFIC2) will not respond to odevixibat.

Liver monitoring

Elevations in liver enzymes and bilirubin levels have been noted in patients treated with odevixibat. Assessment of liver function tests is recommended for patients prior to initiating Bylvay, with monitoring per standard of care.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 5.2). Periodic liver function tests should be considered for patients with severe hepatic impairment.

Diarrhoea

Diarrhoea has been reported as a common adverse reaction when taking odevixibat. Diarrhoea may lead to dehydration. Patients should be monitored regularly to ensure adequate hydration during episodes of diarrhoea (see section 4.8).

Fat-soluble vitamin (FSV) absorption

Assessment of liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase and total bilirubin) is recommended for all patients prior to initiating Bylvay, with monitoring per standard clinical practice.

Lipophilic medicinal products

Assessment of fat-soluble vitamin levels (Vitamins A, D, E) and international normalised ratio (INR) are recommended for all patients prior to initiating Bylvay, with monitoring per standard clinical practice.

Treatment with odevixibat may impact the absorption of fat-soluble medicinal products, including lipophilic oral contraceptives (see sections 4.5 and 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

Transporter-mediated interactions

Odevixibat is a substrate for the efflux transporter P-glycoprotein (P-gp). In adult healthy subjects, co-administration of the strong P-gp inhibitor itraconazole increased the plasma exposure of a single dose of odevixibat 7 200 mcg by approximately 50-60%. This increase is not considered clinically relevant. No other potentially relevant transporter-mediated interactions were identified in vitro (see section 5.2).

Cytochrome P450-mediated interactions

In vitro, odevixibat did not induce CYP enzymes (see section 5.2).

In in vitro studies, odevixibat was shown to be an inhibitor of CYP3A4/5 (see section 5.2).

In adult healthy subjects, concomitant use of odevixibat decreased the area under the curve (AUC) of oral midazolam (a CYP3A4 substrate) by 30% and 1-OH-midazolam exposure by less than 20%, which is not considered clinically relevant.

No interaction studies have been conducted with UDCA and rifampicin.

No interaction studies have been conducted with oral hormonal contraceptives or other lipophilic medicinal products. It cannot be excluded that the absorption of oral contraceptives is affected by concomitant use of odevixibat.

In clinical trials, decreased levels of fat-soluble vitamins were observed in some patients receiving odevixibat. Levels of fat-soluble vitamins should be monitored (see section 4.4).

Paediatric population

No interaction studies have been performed in paediatric patients. No differences are expected between the adult and paediatric populations.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception when treated with Bylvay. Since the uptake of lipophilic oral contraceptives may be affected by odevixibat, a barrier contraceptive method should be used (see section 4.4).

Pregnancy

There are no or limited data from the use of odevixibat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Bylvay is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether odevixibat or its metabolites are excreted in human milk. There is insufficient information on the excretion of odevixibat in animal milk (see section 5.3).

A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Bylvay therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).

4.7. Effects on ability to drive and use machines

Bylvay has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reaction was diarrhoea.

Other reported adverse reactions were vomiting and stomach pain, mild to moderate increases in liver function tests, and decreases in vitamin D and E Levels.

Tabulated list of adverse reactions

The table lists adverse reactions identified in clinical trials in patients with PFIC aged between 4 months to 25 years of age (median 3 years 7 months).

Adverse reactions are ranked according to system organ class, using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

Table 2: Frequency of adverse reactions in PFIC patients

MedDRA system organ class

Frequency

Adverse reaction

Gastrointestinal disorders

Very common

diarrhoeaa, vomiting

abdominal painb

Hepatobiliary disorders

Very common

Blood bilirubin increased

Alanine aminotransferase increased

Common

Hepatomegaly

Aspartate aminotransferase increased

Metabolism and nutrition site disorders

Very common

Vitamin D deficiency

Common

Vitamin E deficiency

a Based on the combined frequency of diarrhoea, diarrhoea haemorrhagic and faeces soft

b Includes abdominal pain upper and abdominal pain lower

Table 3: Frequency of adverse reactions in ALGS patients

MedDRA system organ class

Frequency

Adverse reaction

Gastrointestinal disorders

Very common

Diarrhoea, abdominal paina

Common

Vomiting

Hepatobiliary disorders

Common

Hepatomegaly, alanine aminostransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, blood bilirubin increased

Metabolism and nutrition site disorder

Very Common

Vitamin D deficiency

Common

Vitamin E deficiency

a Includes abdominal pain upper

Description of selected adverse reactions

PFIC

Gastrointestinal adverse reactions

In clinical trials, diarrhoea was the most common gastrointestinal adverse drug reactions. Adverse drug reactions of diarrhoea, diarrhoea haemorrhagic and faeces soft were of short duration with most events ≤ 5 days in duration. Most cases of diarrhoea were mild to moderate in intensity and non-serious.. Dose reduction, treatment interruption and discontinuation due to diarrhoea was reported with few patients requiring intravenous or oral hydration due to diarrhoea (see section 4.4).

Other commonly reported gastrointestinal disorders were vomiting and abdominal pain (including abdominal pain upper and lower), all non-serious, mild to moderate and in general not dose limiting.

ALGS

Most frequently reported adverse drug reaction was diarrhoea, mostly mild in severity and non-serious. Few patients required treatment interruption and rehydration due to diarrhoea (see section 4.4). Other gastrointestinal adverse reactions were reported of abdominal pain and vomiting, mild to moderate in severity and in most cases of limited duration.

Hepatobiliary disorders

PFIC

The most common hepatic adverse reactions were increases in blood bilirubin, aspartate aminotransferase and alanine aminotransferase (AST and ALT). Majority of these were mild to moderate in severity. Treatment interruption due to increases in liver function tests have been seen in patients with PFIC treated with odevixibat. Most excursions in ALT, AST, and bilirubin values were also considered related to the underlying disease, as well as to intermittent concomitant viral or infectious illnesses, which are common at the age of the patients, hence, monitoring of liver function tests is recommended (see section 4.4).

ALGS

The most common hepatic adverse reactions were increases in blood bilirubin, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase. (ALT, AST and GGT). Most of these excursions were mild in severity and non-serious, and increases were not indicative of drug-induced liver injury. Elevations in liver enzymes and bilirubin levels were observed due to the underlying hepatic pathophysiology of ALGS, hence the monitoring of liver function tests is recommended (see section 4.4).

Metabolism and nutrition disorders

PFIC

Due to decreased release of bile acids into the intestine and malabsorption, patients with PFIC are at risk for fat-soluble vitamin deficiency (see section 4.4). Reductions in vitamin levels were observed during long-term treatment with odevixibat; the majority of these patients responded to appropriate vitamin supplementation. Overall, few patients had fat-soluble vitamin deficiency that was refractory to supplementation. These events were mild in intensity and did not lead to discontinuation of odevixibat.

ALGS

Due to the decreased release of bile acids into the intestine and risk of malabsorption, paediatric patients with ALGS with chronic cholestasis are at risk of fat-soluble vitamin deficiencies even with supplementation (see section 4.4). Reductions in vitamin levels were observed during long-term treatment with odevixibat; the majority of these patients responded to appropriate vitamin supplementation. Overall, few patients had fat-soluble vitamin deficiencies that were refractory to supplementation. These events were mild in intensity and did not lead to treatment interruption or discontinuation of odevixibat.

Post-marketing experience

In post-marketing, gastrointestinal disorders and investigations have been most frequently reported adverse reactions. Data are insufficient to provide an estimate of incidence in the PFIC population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

An overdose may result in symptoms resulting from an exaggeration of the known pharmacodynamic effects of the medicinal product, mainly diarrhoea and gastrointestinal effects.

The maximum dose administered to healthy subjects in clinical trials was odevixibat 10 000 mcg as a single dose, without any adverse consequences.

In the event of an overdose, the patient should be treated symptomatically and supportive measures instituted as required.