BYLVAY 600mcg capsules medication leaflet

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.

Hard capsule

Bylvay 200 mcg hard capsules

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

Bylvay 1 200 mcg hard capsules

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

Bylvay is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patientsaged 6 months or older (see sections 4.4 and 5.1).

Treatment must be initiated and supervised by physicians experienced in the management of PFIC.

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 bodyweight 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 capsules4 to < 7.5 1 or N/A7.5 to < 12.5 2 or 112.5 to < 17.5 3 or N/A17.5 to < 25.5 4 or 225.5 to < 35.5 6 or 335.5 to < 45.5 8 or 445.5 to < 55.5 10 or 5≥ 55.5 12 or 6

Capsule strength/number in bold is recommended based on predicted ease of administration.

Improvement in pruritus and reduction of serum bile acid levels may occur gradually in some patientsafter initiating odevixibat therapy. If an adequate clinical response has not been achieved after3 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 bodyweight 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 mcgcapsules4 to < 7.5 1 or N/A7.5 to < 12.5 2 or 112.5 to < 17.5 3 or N/A17.5 to < 25.5 4 or 225.5 to < 35.5 6 or 335.5 to < 45.5 8 or 445.5 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 beestablished following 6 months of continuous daily treatment with odevixibat.

If a dose of odevixibat is missed, the patient should take the forgotten dose as soon as possible withoutexceeding one dose per day.

There are no available clinical data for the use of odevixibat patients with moderate or severe renalimpairment or end-stage renal disease (ESRD) requiring haemodialysis (see section 5.2). However,due to the negligible renal excretion, no dose adjustment is required for patients with mild or moderaterenal impairment.

No dose adjustment is required for patients with mild or moderate hepatic impairment (see sections 5.1and 5.2). Odevixibat has not been sufficiently studied in patients with severe hepatic impairment(Child Pugh C). Due to minimal absorption, no dose adjustment is required, however, additionalmonitoring for adverse reactions may be warranted in these patients when odevixibat is administered(see section 4.4).

The safety and efficacy of odevixibat in children aged less than 6 months has not been established. Nodata are available.

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 or in aliquid but may be swallowed whole.

The smaller 400 mcg and 1 200 mcg capsules are intended to be swallowed whole but may be openedand 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 waterin 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, oatmealporridge, 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 emptythe pellets into the bowl of soft food. The capsule should be gently tapped to ensure that allpellets 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 emptythe pellets into a small mixing cup. The capsule should be gently tapped to ensure that all pelletswill 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, orwater). 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 plungerof the syringe up slowly to withdraw the liquid/pellet mixture into the syringe. Gently push theplunger down again to expel the liquid/pellet mixture back into the mixing cup. Repeat this 2 to3 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 ofthe mouth, and then gently push the plunger down to squirt the liquid/pellet mixture between thechild's tongue and the side of the mouth. Do not squirt liquid/pellet in the back of the child'sthroat because this could cause gagging or choking.

* if any pellet/liquid mixture remains in the mixing cup, repeat the previous step until the entiredose 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.

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

Enterohepatic circulation

The mechanism of action of odevixibat requires that the enterohepatic circulation of bile acids and bilesalt transport into biliary canaliculi is preserved. Conditions, medications or surgical procedures thatimpair either gastrointestinal motility, or enterohepatic circulation of bile acids, including bile salttransport 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.

There are limited clinical data with odevixibat in PFIC subtypes other than 1 and 2.

Diarrhoea has been reported as a common adverse reaction when taking odevixibat. Diarrhoea maylead to dehydration. Patients should be monitored regularly to ensure adequate hydration duringepisodes of diarrhoea (see section 4.8). Treatment interruption or discontinuation may be required forpersistent diarrhoea.

Elevations in liver enzymes and bilirubin levels have been observed in patients treated withodevixibat. Assessment of liver function tests is recommended for all patients prior to initiatingodevixibat, with monitoring per standard clinical practice. For patients with liver function testelevations and severe hepatic impairment (Child-Pugh C), more frequent monitoring is to beconsidered.

Fat-soluble vitamin absorption

Assessment of fat-soluble vitamin (FSV) levels (Vitamins A, D, E) and international normalised ratio(INR) are recommended for all patients prior to initiating odevixibat, with monitoring per standardclinical practice. If FSV deficiency is diagnosed, supplemental therapy should be prescribed.

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 doseof 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 (seesection 5.2).

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) oforal 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.

In an interaction study with a lipophilic combination oral contraceptive containing ethinyl estradiol(EE) (0.03 mg) and levonorgestrel (LVN) (0.15 mg) conducted in adult healthy females, concomitantuse of odevixibat had no impact on the AUC of LVN and decreased the AUC of EE by 17%, which isnot considered clinically relevant. Interaction studies with other lipophilic medicinal products have notbeen performed, therefore, an effect on the absorption of other fat-soluble medicinal products cannotbe excluded.

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

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

Women of childbearing potential should use an effective method of contraception when treated withodevixibat.

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

It is unknown whether odevixibat or its metabolites are excreted in human milk. There is insufficientinformation 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 discontinuebreast-feeding or to discontinue/abstain from odevixibat therapy, taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the mother.

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

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

The most commonly reported adverse reaction was diarrhoea (32.2%). Other reported adverse reactionswere mild to moderate increases in blood bilirubin (24.8%), ALT (14%) and AST (9.1%), vomiting(16.5%), stomach pain (11.6%), and decreases in Vitamin D (11%) and E levels (5%).

The table lists adverse reactions identified in clinical trials in patients with PFIC aged between4 months to 25 years of age (median 3 years 7 months).

Adverse reactions are ranked according to system organ class, using the following convention: verycommon (≥ 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

MedDRA system organ class Frequency Adverse drug reaction

Gastrointestinal disorders Very common diarrhoeaa,vomitingabdominal painb

Hepatobiliary disorders Very common blood bilirubin increased,

ALT increased

Common hepatomegaly,

AST increased

Metabolism and nutrition site Very common vitamin D deficiencydisorders Common vitamin E deficiencya Based on the combined frequency of diarrhoea, diarrhoea haemorrhagic and faeces softb Includes abdominal pain upper and abdominal pain lower

ALT = alanine aminotransferase

AST = aspartate aminotransferase

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

Other commonly reported gastrointestinal disorders were vomiting and abdominal pain (includingupper and lower abdominal pain), all non-serious, mild to moderate and in general not requiring doseadaption.

The most common hepatic adverse reactions were increases in blood bilirubin, AST and ALT. Themajority of these were mild to moderate in severity. Treatment interruption due to increases in liverfunction tests were noted in patients with PFIC treated with odevixibat. Most excursions in ALT, AST,and bilirubin values were also due to the underlying disease, as well as to intermittent concomitantviral or infectious illnesses, which are common at the age of the patients, hence, monitoring of liverfunction tests is recommended (see section 4.4).

Due to decreased release of bile acids into the intestine and malabsorption, patients with PFIC are atrisk for fat-soluble vitamin deficiency (see section 4.4). Reductions in vitamin levels were observedduring long-term treatment with odevixibat; the majority of these patients responded to appropriatevitamin supplementation. These events were mild in intensity and did not lead to discontinuation ofodevixibat.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

An overdose may result in symptoms resulting from an exaggeration of the known pharmacodynamiceffects 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 asingle dose, without any adverse consequences.

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

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy, ATC code: A05AX05

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).

Odevixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase theclearance of bile acids through the colon, reducing the concentration of bile acids in the serum. Theextent of reduction of serum bile acids does not correlate with systemic PK.

The efficacy of Bylvay in patients with PFIC was evaluated in two phase 3 trials and in a Phase 2dose-finding study (A4250-003) in paediatric patients with cholestatic liver disease, including PFIC.

Study A4250-005 was a 24-week, randomised, double-blind, placebo-controlled trial conducted in62 patients with a confirmed diagnosis of PFIC Type 1 or Type 2. Patients were randomised 1:1:1 toplacebo, or 40 or 120 mcg/kg/day odevixibat and stratified by PFIC Type (1 or 2) and age (6 monthsto 5 years, 6 to 12 years, and 13 to ≤ 18 years). Patients with pathologic variations of the ABCB11gene that predict complete absence of the BSEP protein and those with ALT > 10 × ULN or bilirubin> 10 × ULN were excluded. 13% of the patients had prior biliary diversion surgery. Patientscompleting Study A4250-005 were eligible to enrol in Study A4250-008, a 72-week open-labelextension trial. In total, 116 patients were enrolled in Study A4250-008, including 37 patients whoreceived odevixibat in Study A4250-005 and 79 patients who were treatment naïve. Results wereanalysed for Study A4250-005 and pooled for Studies A4250-005 and A4250-008, representing 96weeks of treatment for patients that completed treatment with odevixibat in both trials. The primaryendpoint in Studies A4250-005 and A4250-008 was the proportion of patients with at least a 70%reduction in fasting serum bile acid levels or who achieved a level ≤ 70 µmol/L at week 24.

The proportion of positive pruritus assessments at the patient level over the 24-week treatment periodbased on an observer-reported outcome (ObsRO) instrument was a secondary endpoint. A positivepruritus assessment was a score of ≤ 1 or at least 1-point improvement from baseline. Pruritusassessments were conducted in the morning and evening using a 5-point scale (0-4). Additionalsecondary endpoints included changes from baseline to end of treatment in growth, sleep parameters(per ObsRO) and ALT.

Median (range) age of patients in Study A4250-005 was 3.2 (0.5 to 15.9) years; 50% were male and84% were white. 27% of patients had PFIC Type 1 and 73% had PFIC Type 2. At baseline, 81% ofpatients were treated with UDCA, 66% with rifampicin, and 89% with UDCA and/or rifampicin.

Baseline hepatic impairment per Child-Pugh classification was mild in 66% and moderate in 34% ofpatients. Baseline mean (SD) eGFR was 164 (30.6) mL/min/1.73 m². Baseline mean (SD) ALT, ASTand bilirubin levels were 99 (116.8) U/L, 101 (69.8) U/L, and 3.2 (3.57) mg/dL, respectively. Baselinemean (SD) pruritus score (range: 0-4) and serum bile acids levels were similar in odevixibat-treatedpatients (2.9 [0.089] and 252.1 [103.0] µmol/L, respectively) and placebo-treated patients (3.0 [0.143]and 247.5 [101.1] µmol/L, respectively). Demographic and baseline characteristics of the pooled phase3 population were generally consistent with the Study A4250-005 population. 36 (30%) of patientshad PFIC Type 1, 70 (58%) had PFIC Type 2, 7 (6%) had PFIC Type 3, 4 (3%) had the episodic formof PFIC, and 2 (2%) each had PFIC Type 4 and PFIC Type 6.

Table 4 presents the results of the comparison of the key efficacy results in Study A4250-005 betweenodevixibat and placebo. These data are displayed graphically over the 24-week treatment period in

Figure 1 (serum bile acids) and Figure 2 (scratching scores).

Table 4: Comparison of key efficacy results for odevixibat vs. placebo over the 24-weektreatment period in patients with PFIC in Study A4250-005

Odevixibat

Placebo 40 mcg/kg/day 120 mcg/kg/day Total

Efficacy endpoint (N=20) (N=23) (N=19) (N=42)

Proportion of patients with reduction in serum bile acids at end of treatment (respondersa)n (%) 0 10 (43.5) 4 (21.1) 14 (33.3)(95% CI) (0.00, 16.84) (23.19, 65.51) (6.05, 45.57) (19.57, 49.55)

Difference in proportionvs. placebo 0.44 0.21 0.33(95% CI) (0.22, 0.66) (0.02, 0.46) (0.09, 0.50)

One-sided p-valueb 0.0015 0.0174 0.0015

Proportion of positive pruritus assessments over the treatment period

Proportion 28.74 58.31 47.69 53.51

Difference in proportion 28.23 (9.18) 21.71 (9.89) 24.97 (8.24)(SE) vs. placebo (95% (9.83, 46.64) (1.87, 41.54) (8.45, 41.49)

CI)ca Responders were defined as at least a 70% reduction in serum bile acids concentration from baseline orreaching a level ≤ 70 µmol/L.bBased on Cochran Mantel Haenszel test stratified by PFIC Type. P-values for the dose groups are adjusted formultiplicity.cBased on least squares means from an analysis of covariance model with daytime and night-time baselinepruritus scores as covariates and treatment group and stratification factors (PFIC Type and age category) as fixedeffects.

Figure 1: Mean (±SE) change from baseline in serum bile acid concentration (µmol/L) overtime

Placebo Odevixibat 40 mcg/kg/day Odevixibat 120 mcg/kg/day Odevixibat All Doses

N=20 N=23 N=19 N=420 4 8 12 16 18 20 22 24

Weeks

Number of Patients

Placebo 20 20 18 17 16 12 1140 mcg/kg/day 23 21 21 20 15 14 17120 mcg/kg/day 19 19 16 16 11 11 15

All doses 42 40 37 36 26 25 32

Mean (SE) of Changefrom Baseline

Figure 2: Mean (±SE) change from baseline in pruritus (scratching) severity score over time

Placebo Odevixibat 40 mcg/kg/day Odevixibat 120 mcg/kg/day Odevixibat All Doses0.5 N=20 N=23 N=19 N=420.0

- 0.5

- 1.0

- 1.5

- 2.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Weeks

Number of Patients

Placebo 2020 20 20 20 20 20 20 20 20 20 20 20 18 18 17 17 17 16 15 15 15 15 13 1240 mcg/kg/day 23 23 23 23 23 23 23 22 22 23 23 23 23 19 19 19 19 20 19 18 19 19 19 19 17120 mcg/kg/day 19 19 19 19 19 19 19 19 19 18 18 18 18 16 16 16 16 16 16 16 16 16 16 15 14

All doses 42 42 42 42 42 42 42 41 41 41 41 41 41 35 35 35 35 36 35 34 35 35 35 34 31

In line with the results for reduction of pruritus (scratching), odevixibat reduced the percentage of daysthe patient required soothing, and patients less often required help falling asleep and had fewer daysneeding to sleep with a caregiver. Treatment with odevixibat also led to improvements from baselinein liver function test results (Table 5). The effect of odevixibat on growth parameters over 24 weeks isalso presented.

Mean (SE) of Changefrom Baseline

Table 5: Comparison of efficacy results for growth and hepatic biochemical parameters forodevixibat vs. placebo over the 24-week treatment period in patients with PFIC in

Study A4250-005

Odevixibat

Placebo 40 mcg/kg/day 120 mcg/kg/day Total

Efficacy endpoint (N=20) (N=23) (N=19) (N=42)

Alanine aminotransferase (U/L) (mean [SE])

Baseline 76.9 (12.57) 127.7 (34.57) 89.1 (19.95) 110.2 (20.96)

Change to Week 24 3.7 (4.95) -27.9 (17.97) -25.3 (22.47) -26.7 (13.98)

Mean difference vs. -14.8 (16.63) -14.9 (17.25) -14.8 (15.05)placebo (95% CI)a (-48.3, 18.7) (-49.6, 19.9) (-45.1, 15.4)

Aspartate aminotransferase (U/L) (mean [SE])

Baseline 90.2 (11.59) 114.2 (17.24) 96.0 (16.13) 106.0 (11.87)

Change to Week 24 4.7 (5.84) -36.7 (12.21) -27.0 (19.42) -32.1 (11.02)

Total bilirubin (µmol/L) (mean [SE])

Baseline 53.3 (12.97) 52.2 (10.13) 57.0 (18.05) 54.4 (9.75)

Change to Week 24 -9.6 (15.16) -23.7 (9.23) -19.3 (13.62) -21.7 (7.92)

Height z-scores (mean [SE])

Baseline -2.26 (0.34) -1.45 (0.27) -2.09 (0.37) -1.74 (0.23)

Change to Week 24 -0.16 (0.10) 0.05 (0.11) 0.00 (0.16) 0.03 (0.09)

Mean difference vs. 0.32 (0.16) 0.15 (0.17) 0.24 (0.14)placebo (95% CI)a (0.00, 0.65) (-0.18, 0.48) (-0.05, 0.53)

Weight z-scores (mean [SE])

Baseline -1.52 (0.32) -0.74 (0.27) -1.19 (0.35) -0.94 (0.21)

Change to Week 24 0.10 (0.10) 0.29 (0.11) 0.15 (0.12) 0.22 (0.08)

Mean difference vs. 0.28 (0.14) 0.08 (0.15) 0.18 (0.13)placebo (95% CI)a (-0.01, 0.57) (-0.22, 0.37) (-0.08, 0.44)aBased on least squares means from a mixed model for repeated measures (MMRM) with baseline value as acovariate, and treatment group, visit, treatment-by-visit interaction, treatment-by-baseline interaction andstratification factors (PFIC type and age category) as fixed effects.

In the pooled phase 3 analysis, median duration of exposure across the 121 patients having received atleast one dose of odevixibat was 102.0 weeks. 87 (72%) of the 121 patients received ≥72 weeks oftreatment with odevixibat.

At week 24, 36% of patients were serum bile acids responders (N=112); this effect was sustained atweek 72 when 44% were serum bile acids responders (N=85). Pruritus scores improved in a consistentfashion by 63.5% at week 24 (N=102) and 72.3%, at week 72 (N=76).

The rate of serum bile acid responders at week 72 for patients with PFIC1 was 25% (7 of 28 patients),49% (22 of 45) for PFIC2 and 67% (8 of 12) for patients with other types of PFIC. Positive pruritusassessments at the patient level over 72 weeks was similar in patients with PFIC1 (n=24) and PFIC2(n=43), with response rates of 69% and 70%, respectively. In the subgroup of patients with other typesof PFIC (PFIC3, PFIC4, PFIC6 and episodic PFIC, n=9) 91% were responders.

Mean (SD) changes from baseline at week 72 in ALT, AST, and total bilirubin in the pooled phase 3group were -25.88 (119.18) U/L (n=78), -9.38 (69.279) U/L (N=79), and -25.65 (120.708) µmol/L(1.50 mg/dL) (n=79), respectively. Results for GGT were variable. Consistent and substantialimprovement in growth was observed during longer term treatment with odevixibat. Mean height andweight z-scores improved to -1.26 and -0.75 at week 72, respectively, representing mean (SD) changesof 0.44 (0.705) (n=76) and 0.42 (0.762) (n=77), respectively.

This medicinal product has been authorised under ‘Exceptional Circumstances’. This means that dueto the rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

Odevixibat is minimally absorbed following oral administration; absolute bioavailability data inhumans are not available, and estimated relative bioavailability is < 1%. Peak odevixibat plasmaconcentration (Cmax) is reached within 1 to 5 hours. Simulated Cmax values in a paediatric PFIC patientpopulation 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 × h/mL and 5.99 ng × h/mL, respectively. There is minimal accumulation ofodevixibat following once-daily dosing.

Systemic exposure of odevixibat does not predict efficacy. Therefore, no dose adjustment for foodeffects is considered necessary. Concomitant administration of a high-fat meal (800 - 1 000 calorieswith approximately 50% of total caloric content of the meal from fat) resulted in decreases ofapproximately 72% and 62% in Cmax and AUC0-24, respectively, compared to administration underfasted 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 fastedconditions. Taking into account the lack of PK/PD relationship and need for sprinkling the odevixibatcapsule contents on food for younger children, odevixibat can be administered with food.

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

Odevixibat is minimally metabolised in humans.

Following administration of a single oral dose of 3 000 mcg of radiolabeled odevixibat in healthyadults, 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 unchangedodevixibat.

The mean body weight normalised apparent total clearances CL/F in paediatric patients for the 40 and120 mcg/kg/day dose regimens are 26.4 and 23.0 L/kg/h, respectively, and the mean half-life isapproximately 2.5 hours.

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

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

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

The majority of patients with PFIC presented with some degree of hepatic impairment because of thedisease. 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 notdemonstrate a clinically important impact of mildly impaired hepatic function (Child Pugh A) on thepharmacokinetics of odevixibat. Although, body weight adjusted CL/F values were lower and bodyweight adjusted V/F values were larger in paediatric patients with PFIC with Child Pugh B comparedto healthy subjects, the safety profile was comparable between the patient groups. Patients with severehepatic impairment (Child-Pugh C) have not been studied.

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

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

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

Odevixibat is not a BCRP substrate.

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

In pregnant New Zealand White rabbits, early delivery/abortion was observed in two rabbits receivingodevixibat during the period of foetal organogenesis at an exposure multiple of ≥ 2.3 of the anticipatedclinical exposure (based on total plasma odevixibat AUC0-24). Reductions in maternal body weight andfood consumption were noted in all dose groups (transient at the exposure multiple 1.1 of theanticipated dose).

Starting from the exposure multiple of 1.1 of the clinical human exposure (based on total plasmaodevixibat AUC0-24), 7 foetuses (1.3% of all foetuses from odevixibat exposed does) in all dose groupswere found to have cardiovascular defects (i.e. ventricular diverticulum, small ventricle and dilatedaortic arch). No such malformations were observed when odevixibat was administered to pregnantrats. Because of the findings in rabbits, an effect of odevixibat on cardiovascular development cannotbe excluded.

Odevixibat had no effect on the reproductive performance, fertility, embryo-foetal development, orprenatal/postnatal development studies in rats at the exposure multiple of 133 of the anticipatedclinical exposure (based on total plasma odevixibat AUC0-24), including juveniles (exposure multipleof 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 wasdemonstrated in the pups of lactating dams in the pre- and post-natal developmental toxicity studywith rats (3.2-52.1% of the odevixibat plasma concentration of the lactating dams). It is thereforepossible that odevixibat is present in breast milk.

Microcrystalline cellulose

Hypromellose Ph.Eur

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Shellac

Black iron oxide (E172)

Not applicable.

4 years

Store in the original package in order to protect from light. Do not store above 25 °C.

High-density polyethylene (HDPE) bottle with a tamper evident, child resistant polypropylene closure.

Pack size: 30 hard capsules

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

Ipsen Pharma70 rue Balard75015 Paris

France

EU/1/21/1566/001

EU/1/21/1566/002

EU/1/21/1566/003

EU/1/21/1566/004

Date of first authorisation: 16 July 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.