Bylvay - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Bylvay 200 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 200 micrograms odevixibat

Bylvay 400 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 400 micrograms odevixibat

Bylvay 600 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 600 micrograms odevixibat

Bylvay 1 200 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 1 200 micrograms odevixibat

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule

Bylvay 200 mcg hard capsules

Size 0 capsule (21.7 mm x 7.64 mm) with ivory opaque cap and white opaque body; imprinted “A200” with black ink.

Bylvay 400 mcg hard capsules

Size 3 capsule (15.9 mm x 5.82 mm) with orange opaque cap and white opaque body; imprinted “A400” with black ink.

Bylvay 600 mcg hard capsules

Size 0 capsule (21.7 mm x 7.64 mm) with ivory opaque cap and body; imprinted “A600” with black ink.

Bylvay 1 200 mcg hard capsules

Size 3 capsule (15.9 mm x 5.82 mm) with orange opaque cap and body; imprinted “A1200” with black ink.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Bylvay is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older (see sections 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.

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.

• 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

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

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.

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 in children aged less than 6 months has not been established. No data are available.

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.

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

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.

There are limited or no clinical data with odevixibat in PFIC subtypes other than 1 and 2.

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 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).

In clinical trials, increased levels in liver function tests were observed in some patients receiving odevixibat. 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.

For patients with liver function test elevations, more frequent monitoring should be considered.

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, coadministration 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 breastfeeding 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 reported in (7%) of patients.

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 3: Frequency of adverse reactions in PFIC patients

aIncludes abdominal pain upper

Description of selected adverse reactions

Gastrointestinal adverse reactions

Gastrointestinal adverse reactions occurred at a frequency of 11% in patients treated with Bylvay. Adverse reactions of diarrhoea, abdominal pain and faeces soft were of short duration with most events < 5 days in duration; median time to first onset was 16 days. All reports were mild to moderate in severity and non-serious. Two patients experienced an adverse reaction of clinically significant diarrhoea defined as diarrhoea that persisted for 21 or more days without any other aetiology, was severe in intensity, required hospitalisation or was considered an important medical event, or presented with concurrent dehydration requiring treatment with oral or intravenous rehydration and/or other treatment intervention (see section 4.4). Treatment interruption was reported for diarrhoea in 4% of patients and discontinuation of Bylvay due to diarrhoea was reported in 1%.

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 national reporting system listed in

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

Absorption

Odevixibat is minimally absorbed following oral administration; absolute bioavailability data in humans are not available, and estimated relative bioavailability is < 1%. Peak odevixibat plasma concentration (Cmax) is reached within 1 to 5 hours. Simulated Cmax values in a paediatric PFIC patient population for the 40 and 120 mcg/kg/day doses are 0.211 ng/mL and 0.623 ng/mL, respectively, and AUC values were 2.26 ng x h/mL and 5.99 ng x h/mL, respectively. There is minimal accumulation of odevixibat following once-daily dosing.

Effect of food

Systemic exposure of odevixibat does not predict efficacy. Therefore, no dose adjustment for food effects is considered necessary. Concomitant administration of a high-fat meal (800 – 1 000 calories with approximately 50% of total caloric content of the meal from fat) resulted in decreases of approximately 72% and 62% in Cmax and AUC0–24, respectively, compared to administration under fasted conditions. When odevixibat was sprinkled on apple sauce, decreases of approximately 39% and 36% in Cmax and AUC0–24, respectively, were observed compared to administration under fasted conditions. Taking into account the lack of PK/PD relationship and need for sprinkling the odevixibat capsule contents on food for younger children, odevixibat can be administered with food.

Distribution

Odevixibat is more than 99% bound to human plasma proteins. The mean body weight adjusted apparent volumes of distribution (V/F) in paediatric patients for the 40 and 120 mcg/kg/day dose regimens are 40.3 and 43.7 L/kg, respectively.

Biotransformation

Odevixibat is minimally metabolised in humans.

Elimination

Following administration of a single oral dose of 3 000 mcg of radiolabeled odevixibat in healthy adults, the average percent recovery of the administered dose was 82.9% in faeces; less than 0.002% was recovered in the urine. More than 97% of faecal radioactivity was determined to be unchanged odevixibat.

The mean body weight normalised apparent total clearances CL/F in paediatric patients for the 40 and 120 mcg/kg/day dose regimens are 26.4 and 23.0 L/kg/h, respectively, and the mean half-life is approximately 2.5 hours.

Linearity/non-linearity

The Cmax and AUC0-t increase with increasing doses in a dose-proportional manner; however due to the high interindividual variability of approximately 40%, it is not possible to estimate the dose proportionality accurately.

Pharmacokinetic/phar­macodynamic relationship(s)

Consistent with the mechanism and site of action of odevixibat in the gastrointestinal tract no relationship between systemic exposure and clinical effects is observed. Also, no dose-response relationship could be established for the investigated dose range 10–200 mcg/kg/day and the PD parameters C4 and FGF19.

Special populations

No clinically significant differences in the pharmacokinetics of odevixibat were observed based on age, sex or race.

Hepatic impairment

The majority of patients with PFIC presented with some degree of hepatic impairment because of the disease. Hepatic metabolism of odevixibat is not a major component of the elimination of odevixibat. Analysis of data from a placebo-controlled study in patients with PFIC Types 1 and 2 did not demonstrate a clinically important impact of mildly impaired hepatic function (Child Pugh A) on the pharmacokinetics of odevixibat. Although, body weight adjusted CL/F values were lower and body weight adjusted V/F values were larger in paediatric patients with PFIC with Child Pugh B compared to healthy subjects, the safety profile was comparable between the patient groups. Patients with severe hepatic impairment (Child-Pugh C) have not been studied.

Renal impairment

There are no clinical data in patients with renal impairment, but the impact of renal impairment is expected to be small due to low systemic exposure and odevixibat is not excreted in urine.

In vitro studies

In in vitro studies, odevixibat did not inhibit CYPs 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations, but was shown to be an inhibitor of CYP3A4/5.

Odevixibat does not inhibit the transporters P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OATP1B1, OATP1B3, OAT1, OAT3), organic cation transporter (OCT2), multidrug and toxin extrusion transporter (MATE1 or MATE2-K).

Odevixibat is not a BCRP substrate.

5.3 Preclinical safety data

Adverse reactions not observed in clinical trials, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Reproductive and developmental toxicity

In pregnant New Zealand White rabbits, early delivery/abortion was observed in two rabbits receiving odevixibat during the period of foetal organogenesis at an exposure multiple of > 2.3 of the anticipated clinical exposure (based on total plasma odevixibat AUC0–24). Reductions in maternal body weight and food consumption were noted in all dose groups (transient at the exposure multiple 1.1 of the anticipated dose).

Starting from the exposure multiple of 1.1 of the clinical human exposure (based on total plasma odevixibat AUC0–24), 7 foetuses (1.3% of all foetuses from odevixibat exposed does) in all dose groups were found to have cardiovascular defects (i.e. ventricular diverticulum, small ventricle and dilated aortic arch). No such malformations were observed when odevixibat was administered to pregnant rats. Because of the findings in rabbits, an effect of odevixibat on cardiovascular development cannot be excluded.

Odevixibat had no effect on the reproductive performance, fertility, embryo-foetal development, or prenatal/postnatal development studies in rats at the exposure multiple of 133 of the anticipated clinical exposure (based on total plasma odevixibat AUC0–24), including juveniles (exposure multiple of 63 of the anticipated human exposure).

There is insufficient information on the excretion of odevixibat in animal milk.

The presence of odevixibat in breast milk was not measured in animal studies. Exposure was demonstrated in the pups of lactating dams in the pre- and post-natal developmental toxicity study with rats (3.2–52.1% of the odevixibat plasma concentration of the lactating dams). It is therefore possible that odevixibat is present in breast milk.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Microcrystalline cellulose

Hypromellose Ph.Eur

Capsule shell

Bylvay 200 mcg and 600 mcg hard capsules

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Bylvay 400 mcg and 1 200 mcg hard capsules

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Printing ink

Shellac Ph.Eur

Propylene glycol

Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store in the original package in order to protect from light. This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

High-density polyethylene (HDPE) bottle with a tamper evident, child resistant polypropylene closure. Pack size: 30 hard capsules

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Albireo AB

Arvid Wallgrens backe 20

413 46 Göteborg

Sweden

e-mail:

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1566/001

EU/1/21/1566/002

EU/1/21/1566/003

EU/1/21/1566/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: