KAYFANDA 1200mcg capsules medication leaflet

KAYFANDA 200 microgram hard capsules

KAYFANDA 400 microgram hard capsules

KAYFANDA 600 microgram hard capsules

KAYFANDA 1 200 microgram hard capsules

KAYFANDA 200 mcg hard capsules

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

KAYFANDA 400 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 400 micrograms odevixibat.

KAYFANDA 600 mcg hard capsules

Each hard capsule contains odevixibat sesquihydrate equivalent to 600 micrograms odevixibat.

KAYFANDA 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

KAYFANDA 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.

KAYFANDA 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.

KAYFANDA 600 mcg hard capsules

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

KAYFANDA 1 200 mcg hard capsules

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

KAYFANDA is indicated for the treatment of cholestatic pruritus in Alagille syndrome (ALGS) inpatients aged 6 months or older (see sections 4.4 and 5.1).

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

The recommended dose of odevixibat is 120 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 120 mcg/kg/day dose, with a maximum daily dose of 7 200 mcg per day.

Table 1: Number of odevixibat capsules needed to achieve the nominal dose of 120 mcg/kg/day

Body weight (kg) Total mcg dose Number of 600 mcg Number of 1 200 mcgcapsules capsules4 to < 7.5 600 1 or Not applicable (N/A)7.5 to < 12.5 1 200 2 or 112.5 to < 17.5 1 800 3 or N/A17.5 to < 25.5 2 400 4 or 225.5 to < 35.5 3 600 6 or 335.5 to < 45.5 4 800 8 or 445.5 to < 55.5 6 000 10 or 5≥ 55.5 7 200 12 or 6

Capsule strength/number in bold is recommended based on predicted ease of administration. If necessary, any ofthe four capsule strengths can be combined as needed to achieve the nominal dose.

Dose reduction to 40 mcg/kg/day may be considered if tolerability issues (diarrhoea that lasts≥ 3 days, is considered severe, or requires IV hydration (see section 4.4)) occur in the absence of othercauses. Once tolerability issues stabilise, the dose should be increased to 120 mcg/kg/day.

Table 2 shows the strength and number of capsules that should be administered daily based on bodyweight to approximate a 40 mcg/kg/day dose.

Table 2: Number of odevixibat capsules needed to achieve the nominal dose of 40 mcg/kg/day

Body weight (kg) Total mcg dose Number of 200 mcg Number of 400 mcgcapsules capsules4 to < 7.5 200 1 or N/A7.5 to < 12.5 400 2 or 112.5 to < 17.5 600 3 or N/A17.5 to < 25.5 800 4 or 225.5 to < 35.5 1 200 6 or 335.5 to < 45.5 1 600 8 or 445.5 to < 55.5 2 000 10 or 5≥ 55.5 2 400 12 or 6

Capsule strength/number in bold is recommended based on predicted ease of administration. If necessary, any ofthe four capsule strengths can be combined as needed to achieve the nominal dose.

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.

No dose adjustment is required for patients with mild renal impairment.

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

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. Close monitoring,however, is advised for patients with end-stage liver disease or progression to decompensation (seesection 4.4).

The safety and the efficacy of odevixibat in children aged less than 6 months have not beenestablished. No data are available.

KAYFANDA 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/caregiver 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 patient/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.

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.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase(GGT) and bilirubin level elevations were observed in patients receiving odevixibat (see section 4.8).

Liver function tests should be monitored prior to start and during treatment with odevixibat.

For patients with liver function test elevations and severe hepatic impairment (Child-Pugh C), morefrequent monitoring is to be considered.

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.

Fat-soluble vitamins

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).

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).

Cytochrome (CYP) 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) oforal midazolam (a CYP3A4 substrate) by 30% and 1-OH-midazolam exposure by less than 20%,which is not considered clinically relevant.

Ursodeoxycholic acid (UDCA) and rifampicin

No interaction studies have been conducted with UDCA and rifampicin.

Lipophilic medicinal products

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.

Interaction studies have only been performed in adults. No differences are expected between the adultand 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 in ALGS patients treated with odevixibat in clinical trialswas diarrhoea(36.5%). Other reported adverse reactions were stomach pain (17.3%), mild to moderateincreases in liver function tests (combined incidence of 17.3%) decreases in vitamin D (13.5%) and Elevels (9.6%) and vomiting (5.8%).

Table 3 lists adverse reactions identified in patients with ALGS.

Adverse reactions are ranked according to system organ class and frequency grouping. Frequencies aredefined 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 reported in patients with ALGS

MedDRA system organ class Frequency Adverse reaction

Gastrointestinal disorders Very common diarrhoeaabdominal paina*

Common vomiting*

Hepatobiliary disorders Common hepatomegaly,alanine aminotransferaseincreased*,aspartate aminotransferaseincreased*,gamma-glutamyl transferaseincreased*,blood bilirubin increased*

Metabolism and nutrition site Very common vitamin D deficiency*disorders Common vitamin E deficiency*a Includes abdominal pain upper

*See section ‘Description of selected adverse reactions‘.

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

The most common hepatic adverse reactions were increases in blood bilirubin, ALT, AST and GGT.

Most of these excursions were mild in severity and non-serious, and increases were not indicative ofdrug-induced liver injury. Elevations in liver enzymes and bilirubin levels were observed due to theunderlying hepatic pathophysiology of ALGS, hence the monitoring of liver function tests isrecommended (see section 4.4).

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

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.

The maximum dose administered to healthy adult subjects in clinical trials was odevixibat 10 000 mcgas a single 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 pharmacokinetics (PK).

The efficacy of odevixibat in patients with ALGS was evaluated in two phase 3 trials. Study A4250-012 (ASSERT) was a 24-week, randomised, double-blind, placebo-controlled trial conducted in52 patients with a confirmed diagnosis of ALGS. Patients were randomised 2:1 to 120 mcg/kg/dayodevixibat or placebo and stratified by age at randomisation (< 10 years and ≥ 10 to < 18 years).

Patients whose ALT was > 10 × upper limit of normal (ULN) or total bilirubin > 15 × ULN atscreening were excluded in the ASSERT trial.

Patients who completed ASSERT trial were eligible to enrol in Study A4250-015 (ASSERT-EXT), a72-week open-label extension trial. Results were analysed for ASSERT, and pooled for the ASSERTand ASSERT-EXT trials, representing 96 weeks of treatment for patients that completed treatmentwith odevixibat in both trials.

The primary endpoint in ASSERT was change in scratching severity score from baseline to month 6(weeks 21 to 24) based on the worst scratching score using an observer-reported outcome (ObsRO)instrument. Scratching was assessed once in the morning and once in the evening using a 5-point scale(0-4).

Change in serum bile acid levels from baseline to the average of weeks 20 and 24 was the keysecondary endpoint. Additional secondary endpoints included change from baseline to end oftreatment in sleep parameters (assessed using a 5-point scale (0-4)), total cholesterol concentration andclinician assessment of xanthomas.

Median age (range) of the patients in ASSERT was 5.45 (0.5 to 15.5) years; 51.9% were male and82.7% were white. 92.3% of patients had the Jagged canonical NOTCH ligand 1 (JAG1) mutation and7.7% had the NOTCH2 mutation. At baseline, 98.1% of patients were treated with concomitant anti-pruritic medications, including UDCA (88.5%). Overall, 51 (98.1%) of the 52 patients had moderatehepatic impairment and 1 (1.9%) (placebo group) had severe hepatic impairment based on the Child-

Pugh C classification. Baseline mean (standard deviation [SD)] estimated glomerular filtration rate(eGFR) was 158.65 (51.437) mL/min/1.73 m2. Baseline mean (SD) ALT, AST, and total bilirubinwere 173.7 (84.48) U/L, 167.0 (83.22) U/L, and 55.14 (47.911) µmol/L, respectively. Baseline mean(SD) scratching score (range: 0-4) and serum bile acid levels were similar in odevixibat-treatedpatients (2.80 [0.520] and 237.4 [114.88] µmol/L, respectively) and placebo-treated patients(3.01 [0.636] and 246.1 [120.53] µmol/L, respectively).

Table 4 presents the results of the change from baseline in average scratching score based on the

ObsRO assessments to month 6 (weeks 21 to 24) and results of the change from baseline in serum bileacids to the average of weeks 20 and 24.

Table 4: Comparison of key efficacy results for odevixibat vs. placebo over the 24-weektreatment period (ASSERT)

Odevixibat

Placebo 120 mcg/kg/day(N=17) (N=35)

Change from baseline in average scratching scorea to month 6 (Weeks 21 to 24) of treatment

LS Mean (95% CI)b -0.80 (-1.27, -0.33) -1.69 (-2.04, -1.34)

LS Mean difference vs. placebo (95% CI) b -0.88 (-1.44, -0.33)

Two-sided p-valueb 0.0025

Change from baseline in serum bile acid concentration (µmol/L) to the average of weeks 20and 24 of treatment

LS Mean (95% CI)b 22.39 (-34.75, 79.52) -90.35 (-1.33, -47.56)

LS Mean difference vs. placebo (95% CI)b -112.74 (-178.78, -46.69)

Two-sided p-valueb 0.0012

CI: confidence interval; LS Mean = Least Squares Meansa Based on the ObsRO instrument which is a validated 0-4 scale completed by caregivers (0=none to 4=verysevere), where changes ≥1.0 have been shown to be clinically meaningful.b The analyses are based on mixed-model effect repeated measures (MMRM) with baseline scratching score orbaseline serum bile acid concentration (as applicable for the endpoint) as a covariate, and baseline agestratification (< 10, ≥ 10 years), baseline direct bilirubin (scratching score only), treatment group, time(months/visits), and treatment-by-time interaction as fixed effects.

Figures 1 and 2 display graphically the mean changes standard error (SE) from baseline of patients’average scratching scores in each treatment group for each week and patients’ serum bile acid levels ineach treatment group for each month, respectively.

Figure 1: Mean (± SE) change from baseline in pruritus (scratching) severity score over time(ASSERT)

Number of Patients

Placebo 17 17 17 16 17 17 17 17 17 17 16 16 16 15 15 16 15 16 17 17 16 16 16 17 16120 μg/kg/day 35 34 35 34 34 35 35 33 34 34 34 34 34 34 33 33 34 35 35 35 33 34 35 33 31

Figure 2: Mean (± SE) change from baseline in serum bile acid concentration (µmol/L) over time(ASSERT)

Placebo Odevixibat 120 μg/kg/day

N=17 N=350 4 8 12 16 20 24 28

Weeks

Number of Patients

Placebo 17 16 15 16 17 15 16 17120 μg/kg/day 35 34 35 35 35 35 33 35

Consistent with the results for improvement in pruritus (scratching) severity, odevixibat led toimprovements in multiple sleep parameters. Figure 3 displays graphically the mean changes (SE) frombaseline for improvement in two of the sleep parameters by treatment group for each month, includingpercentage of days with help falling asleep and daytime tiredness score. Similar results were observedover time for percentage of days the child required soothing to go to sleep and the percentage of daysthe child slept with the caregiver.

Figure 3: Mean (±SE) change from baseline in sleep parameters over time (ASSERT)

Percentage of days with help falling asleep Tiredness score

Placebo Odevixibat 120 μg/kg/day Placebo Odevixibat 120 μg/kg/day

N=17 N=35 N=17 N=3510 00 -0.2

- 10 -0.4

- 20 -0.6

- 30 -0.8

- 40 -1

- 50 -1.2

- 60 -1.40 4 8 12 16 20 24 0 4 8 12 16 20 24

Weeks Weeks

Number of Patients Number of Patients

Placebo 17 17 17 16 15 17 16 Placebo 17 17 17 16 15 17 16120 μg/kg/day 35 33 34 33 34 34 33 120 μg/kg/day 35 34 34 34 33 35 34

Mean (SE) of Change Mean (SE) of Changefrom Baseline from Baseline

Mean (SE) of Changefrom Baseline

A total of 44 (85%) of the 52 patients who received odevixibat across the Phase 3 studies completedthe 72-week treatment period in ASSERT-EXT. Median duration of odevixibat treatment for the52 patients across the pooled phase 3 studies was 99.79 weeks and ranged up to 2.5 years. Overall, 45(87%) of the 52 patients had received > 72 weeks of odevixibat with 32 (64%) having received> 96 weeks of treatment.

Continued treatment with odevixibat 120 mcg/kg/day in ASSERT-EXT led to further improvements inpruritus score with results for the pooled population at weeks 69-72 (n = 43) showing mean (SD)changes from baseline of -1.95 (0.838). For those 31 patients who received odevixibat in both Phase 3studies and had data available for analysis, continued improvement was observed through weeks 93-96with mean (SD) change from baseline of -2.18 (0.876). The reduction in serum bile acid levels wasmaintained at week 72, when mean change from baseline was -119.4 µmol/L (-48.8 µg/mL; n = 44).

Among those 30 patients who received odevixibat in both Phase 3 studies and had data available foranalysis at week 96, change from baseline in serum bile acid levels was -123.9 µmol/L (-50.6 µg/mL).

Improvements in sleep parameters, serum cholesterol levels and xanthomas were maintained duringlong-term treatment.

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. Observed exposures in paediatric patients (agebetween 0.756 and 17.1 years; body weight from 5.6 to 58 kg) are limited to trough values; for the120 mcg/kg/day dose the trough values were below the limit of detection for 40% of the samples in

ALGS patients. The mean Cmax value in a paediatric ALGS patient population for the 120 mcg/kg/daydose is 1.13 ng/mL and the mean AUC value was 13.2 ng × h/mL. No accumulation of odevixibat wasobserved 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/pharmacodynamic (PD) relationship and need forsprinkling the odevixibat capsule contents on food for younger children, odevixibat can beadministered with food.

Odevixibat is more than 99% bound to human plasma proteins. The mean volume of distribution (V/F)in ALGS patients is predicted to be 1160 L. The geometric mean body weight adjusted V/F for ALGSis 57.9 L/kg.

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 apparent clearance (CL/F) in ALGS patients is predicted to be 212 L/h, and the mean half-life is approximately 4.75 hours. The geometric mean body weight adjusted CL/F for ALGS is10.5 L/h/kg.

The Cmax and AUC0-t increase with increasing doses in a dose-proportional manner; however due to thehigh 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 7α-hydroxy-4 cholesten-3 one (C4) and fibroblast growth factor 19 (FGF19).

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

All patients with ALGS presented with some degree of hepatic impairment because of the disease.

Based on population PK analysis, patients with mild hepatic impairment (Child-Pugh A) exhibitedcomparable pharmacokinetics compared to other subjects with normal hepatic function. Patients withmoderate hepatic impairment (Child-Pugh B) presented a 77.0% lower CL/F relative to patients withmild hepatic impairment or no hepatic impairment and exposure of odevixibat was 4- to 9-fold higherin patients with moderate hepatic impairment. The plasma AUC at 120 mcg/kg/day in patients with

Child-Pugh A ranged from 1.52 to 10.4 ng × h/mL and in patients with Child-Pugh B was between5.50 to 74.5 ng × h/mL. Although, CL/F values were lower and V/F values were larger in patients with

Child Pugh B compared to other subjects, no accumulation of odevixibat was observed and the safetyprofile was comparable between the patient groups. No data are available for patients with severehepatic impairment (Child-Pugh C).

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 not being 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 transporters (OATP1B1, OATP1B3, OAT1, OAT3), organic cation transporter (OCT2),multidrug and toxin extrusion transporters (MATE1 or MATE2-K).

Odevixibat is a substrate of gastrointestinal efflux transporter P-gp, but not of BCRP.

Adverse reactions not observed in clinical studies, 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 ≥ 1.6 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 0.5 of theanticipated dose).

Starting from the exposure multiple of 0.5 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 ofodevixibat in breast milk was not measured in animal studies. Exposure was demonstrated in the pupsof lactating dams in the pre- and post-natal developmental toxicity study with rats (3.2-52.1% of theodevixibat plasma concentration of the lactating dams). It is therefore possible that odevixibat ispresent in breast milk.

Microcrystalline cellulose

Hypromellose

KAYFANDA 200 mcg and 600 mcg hard capsules

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

KAYFANDA 400 mcg and 1 200 mcg hard capsules

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/1/24/1854/001

EU/1/24/1854/002

EU/1/24/1854/003

EU/1/24/1854/004

Date of first authorisation: 19 September 2024

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

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