LYVDELZI 10mg capsules medication leaflet

Lyvdelzi 10 mg hard capsules

Each hard capsule contains seladelpar lysine dihydrate equivalent to 10 mg seladelpar.

For the full list of excipients, see section 6.1.

Hard capsules.

Size 1 (26.1 mm x 9.4 mm) hard capsules with dark blue opaque cap and light grey opaque bodyimprinted with “CBAY” in white ink on the cap and “10” in black ink on the body.

Lyvdelzi is indicated for the treatment of primary biliary cholangitis (PBC) in combination withursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or asmonotherapy in those unable to tolerate UDCA.

The recommended dose of seladelpar is 10 mg once daily.

If a dose of seladelpar is missed, the patient should take the subsequent dose at the next scheduledtime point. A double dose should not be taken to make up for the missed dose.

Limited data exists in elderly patients. No dose adjustment is required for elderly patients (see section5.2).

No dose adjustment of seladelpar is required for patients with mild, moderate and severe renalimpairment (see section 5.2).

Patients with end-stage renal disease on dialysis have not been studied. No dose recommendation canbe provided for this group.

No dose adjustment is required in PBC patients with mild hepatic impairment (Child-Pugh A).

Safety and efficacy of seladelpar have not been established in PBC patients with moderate(Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Consider discontinuing seladelpar if the patient progresses to moderate hepatic impairment. Use is notrecommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).

There is no relevant use of seladelpar in the paediatric population in the treatment of PBC.

Oral use. The capsules can be taken with or without food.

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

Liver test abnormalities

Dose dependent increases in serum transaminases (aspartate aminotransferase [AST] and alanineaminotransferase [ALT]) have been observed in patients receiving higher doses of seladelpar (seesection 4.9). Obtain baseline clinical and laboratory assessments at initiation of treatment withseladelpar and monitor thereafter according to routine clinical practice. Consider temporaryinterruption of seladelpar treatment if liver tests worsen, or the patient develops signs and symptomsconsistent with liver dysfunction. Consider permanent discontinuation if liver tests worsen again afterrestarting seladelpar.

Biliary Obstruction

Avoid use of seladelpar in patients with complete biliary obstruction. If biliary obstruction issuspected, interrupt seladelpar and treat as clinically indicated.

Co-administration of probenecid with seladelpar is not recommended (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to sayessentially ‘sodium-free’.

Effect of other medicinal products on seladelpar

Concomitant administration of seladelpar with probenecid (an OAT1, OAT3 and OATP1B1-inhibitor)is not recommended (see section 4.4).

In a dedicated clinical drug interaction study, seladelpar area under the curve from zero to time infinity(AUC0-inf) increased by 2-fold and maximum serum concentration (Cmax) by 4.69-fold followingconcomitant use of a single 10 mg seladelpar dose with 500 mg probenecid in healthy subjects.

Inhibitors of drug transporters

Concomitant administration of seladelpar with dual or multiple clinical inhibitors of drugs transportersincluding BCRP, OATP1B1, OATP1B3 and OAT3 (e.g cyclosporine) may result in an increase ofseladelpar exposure. When seladelpar is concomitantly administered with dual or multiple clinicalinhibitors of drugs transporters including BCRP, OATP1B1, OATP1B3, and OAT3, patients should beclosely monitored for adverse effects.

In a dedicated clinical drug interaction study, seladelpar AUC0-inf increased by 2.1-fold and Cmax by2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg cyclosporine (a

BCRP, OATP1B1, OATP1B3 and CYP3A4 inhibitor) in healthy subjects.

CYP2C9 and CYP3A4 inhibitors

Seladelpar is primarily metabolized in vitro by CYP2C9 and to a lesser extent by CYP2C8 and

CYP3A4. Concomitant administration of seladelpar with medicines that are strong CYP2C9inhibitors, or dual moderate CYP2C9 and moderate-to-strong CYP3A4 inhibitors may result in anincrease in seladelpar exposure. When seladelpar is concomitantly administered with medicinalproducts that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate to strong

CYP3A4 inhibitors (e.g. fluconazole, mifepristone), patients should be closely monitored for adverseeffects.

In a dedicated clinical drug interaction study, seladelpar AUC0-inf increased by 2.4-fold and Cmax by1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole(moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects.

CYP2C9 inducers and strong CYP3A4 inducers

Concomitant administration of seladelpar with medicines that are CYP2C9 inducers and strong

CYP3A4 inducers (e.g. rifampicin, a strong CYP3A4 and moderate CYP2C9 inducer) can decreaseseladelpar exposure. When seladelpar is concomitantly administered with medicinal products that are

CYP2C9 inducers and strong CYP3A4 inducers, patients should be monitored for a potential reductionin efficacy.

Seladelpar AUC0-inf decreased by approximately 44% and Cmax by 24% following administration of asingle 10 mg seladelpar dose after carbamazepine 300 mg twice daily in healthy subjects. Thecarbamazepine (a strong CYP3A and weak CYP2C9 inducer) dose was escalated from 100 mg to300 mg over 7 days.

Bile acid binding resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam, may reduce the absorptionof other medicinal products administered concurrently. Patients should take seladelpar at least 4 hoursbefore or 4 hours after taking a bile acid binding resin.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of seladelparin pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity atclinically relevant exposure levels (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of seladelpar during pregnancy.

It is unknown whether seladelpar or its metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from seladelpar therapy taking into account the benefit of breast-feeding forthe child and the benefit of therapy for the woman.

No human data on the effect of seladelpar on fertility are available.

Animal studies do not indicate any direct or indirect effects on fertility or the ability to reproduce.

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

Based on clinical trial experience, the most frequently reported adverse reactions were abdominal pain(11.1%), headache (7.2%), nausea (6.5%) and abdominal distension (3.9%). These adverse reactionswere non-serious and did not lead to discontinuation of seladelpar.

The frequencies of the adverse drug reactions provided in the table below are based on pooled datafrom the RESPONSE and ENHANCE trials unless otherwise stated.

Frequencies are defined according to 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); not known (cannot be estimated from the available data).

Table 1: Adverse drug reactions reported in clinical trials in patients treated with seladelpar

System Organ Class Very Common Common

Nervous System Disorders Headache

Gastrointestinal Disorders Abdominal paina Nausea

Abdominal distensiona Includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

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.

PBC patients who received 5 times the recommended dose or 20 times the recommended dose ofseladelpar experienced an increase in liver transaminases, muscle pain, and/or elevations in creatinephosphokinase, which resolved upon seladelpar discontinuation. Dose dependent increases in serumcreatinine were also observed.

There is no specific treatment for overdose with seladelpar. General supportive care of the patient isindicated, as appropriate. If indicated, elimination of unabsorbed medicinal product should beachieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.

Because seladelpar is highly bound to plasma proteins, haemodialysis should not be considered.

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy. ATC code: A05AX07

Seladelpar is a peroxisome proliferator-activated receptor delta (PPARδ) agonist, or delpar. PPARδ isa nuclear receptor expressed in the liver and other tissues. PPARδ activation reduces bile acidsynthesis in the liver through Fibroblast Growth Factor 21 (FGF21) -dependent downregulation of

CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol and by decreasingcholesterol synthesis and absorption. These actions result in lower bile acid exposure in the liver andreduced circulating bile acid levels.

In clinical studies, reduction in ALP was observed within 1 week, continued to decrease through

Month 3, and was sustained through Month 24.

In RESPONSE, treatment with seladelpar led to a decrease in Interleukin-31 (IL-31) after 6 and12 months of treatment in patients with moderate to severe pruritus.

The efficacy of seladelpar was evaluated in patients with PBC in a randomised, double-blind,placebo-controlled, 12-month trial (RESPONSE). Patients were included in the trial if their ALP was1.67-times upper limit of normal (ULN) or greater and total bilirubin was less than or equal to 2-times

ULN. Patients were excluded from the trial if they had other chronic liver diseases, clinicallyimportant hepatic decompensation including portal hypertension with complications, or cirrhosis withcomplications (e.g., Model for End Stage Liver Disease [MELD] score of 12 or greater, knownoesophageal varices or history of variceal bleeds, history of hepatorenal syndrome). A 14-day run-inperiod prior to randomisation was used to establish a baseline itch intensity, as measured by thepatient-reported daily 24-hour Numerical Rating Scale (Pruritus-NRS) scores (0 “no itch” to 10 “worstitch imaginable”).

Patients were randomised (2:1) to receive either seladelpar (n = 128) 10 mg once daily; or placebo(n = 65) for 12 months. Seladelpar or placebo was administered in combination with UDCA in 181(94%) patients during the trial, or as a monotherapy in 12 (6%) patients who were unable to tolerate

UDCA.

The two treatment groups were generally balanced with respect to baseline demographics and diseasecharacteristics. Of the 193 randomised patients, the mean age was 56.7 years (range 28-75 years);41 (21%) were aged 65 years or older; 183 (95%) were female; 170 (88%) were White, 11 (6%) were

Asian, 4 (2%) were Black or African American, 6 (3%) were American Indian or Alaska Native. Atotal of 56 (29%) patients identified as Hispanic/Latino.

The mean baseline ALP concentration was 314.3 U/L, corresponding to 2.7-times ULN. The meanbaseline total bilirubin concentration was 0.758 mg/dL and was less than or equal to the ULN in 87%of the enrolled patients. At baseline patients in the study population had the following elevations inother liver biochemistries: alanine aminotransferase (ALT) 1.2-times the ULN, aspartateaminotransferase (AST) 1.2-times the ULN, and gamma-glutamyl transferase (GGT) 1.7-times the

ULN. The baseline mean (SD) pruritus NRS score was 3.0 (2.85). Among enrolled patients, 49 (38%,mean NRS score 6.1) in the seladelpar 10 mg arm and 23 (35%, mean NRS score 6.6) in the placeboarm had moderate to severe pruritus (NRS score ≥ 4) at baseline (mean baseline NRS score 6.3).

Cirrhosis (Child-Pugh A) was present at baseline in 18 patients (14%) in the seladelpar 10 mg arm,and 9 patients (14%) in the placebo arm.

In RESPONSE, the primary endpoint was a responder analysis at Month 12, where response wasdefined as a composite of three criteria: ALP less than 1.67-times the ULN, total bilirubin ≤ ULN, andan ALP decrease of at least 15%. The ULN for ALP was defined as 116 U/L for females and males.

The ULN for total bilirubin was defined as 1.1 mg/dL for females and males. ALP normalisation wasdefined as achieving ALP less than ≤ 1.0-times the ULN. The pruritus improvement was assessed bychange from baseline in weekly averaged pruritus NRS score at Month 6 in patients with NRSscore ≥ 4 at baseline.

The results for the primary composite endpoint and ALP normalisation are presented in Table 2.

Table 2: RESPONSE trial: Composite biochemical endpoint and ALP normalisation withseladelpar with or without UDCAa

Seladelpar 10 mg Placebo Treatment(N = 128) (N = 65) difference% (95% CI)e

Primary composite endpoint at Month 12b

Responder rate, (%)c 62 20 42 (28, 53)[95 % CI] [53, 70] [10, 30]

Components of primary endpoint

ALP less than 1.67-times ULN, (%) 66 26 39 (25, 52)

Decrease in ALP of at least 15%, (%) 84 32 51 (37, 63)

Total bilirubin less than or equal to ULNd, (%) 81 77 4 (-7, 17)

ALP normalisation

ALP normalisation at Month 12, ≤ 1.0×ULN (%)c 25 0 25 (18, 33)[95% CI] [18, 33] [0, 0]

N = Number

CI = Confidence Intervala In the trial there were 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 subjects(6%) in the seladelpar 10 mg arm, and 4 patients (6 %) in the placebo arm.b Percentage of patients achieving a response, defined as an ALP value less than 1.67-times the ULN, an ALP decrease ofat least 15%, and total bilirubin less than or equal to the ULN. Patients with missing values were considered as notachieving response.

c p < 0.0001 for seladelpar 10 mg versus placebo. P-value was obtained using the Cochran-Mantel-Haenszel Teststratified by baseline ALP level < 350 U/L versus ALP level ≥ 350 U/L, and baseline pruritus NRS < 4 versus ≥ 4.

d The mean baseline total bilirubin value was 0.758 mg/dL and was less than or equal to the ULN in 87% of the enrolledpatients.

e 95% unstratified Miettinen and Nurminen confidence intervals (CIs) are provided.

Alkaline phosphatase (ALP)

Figure 1 shows the mean reductions in ALP in seladelpar-treated patients compared to placebo.

Reductions were observed at Month 1, continued through Month 6, and were sustained through

Month 12.

Figure 1: Change from baseline in ALP over 12 months in RESPONSE by treatment arm withor without UDCAa

Placebo n=10 mg n=

Placebo (N=65) Seladelpar 10 mg (N=128)a In the trial there were 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 patients(6%) in the seladelpar 10 mg arm and 4 patients (6%) in the placebo arm.

Among the subset of patients with ALP < 350 U/L (< approximately 3-times ULN) at baseline, 76%(71/93) and 23% (11/47) of patients achieved a response at Month 12, in the seladelpar 10 mg andplacebo arms, respectively. For patients with ALP ≥ 350 U/L at baseline, 23% (8/35) and 11% (2/18)of patients achieved a response at Month 12, in the seladelpar 10 mg and placebo arms, respectively.

Lipid Parameters

The LS means difference from placebo in total cholesterol, LDL-C, and triglycerides was -4.4 (95%

CI: -8.5, -0.3) mg/dL, -9.0 (95% CI: -15.0, -2.9) mg/dL, and -15.1 (95% CI: -22.1, -8.1), respectivelyat month 12. High density lipoprotein-cholesterol remained stable on treatment with seladelpar.

Pruritus

Seladelpar significantly reduced pruritus compared to placebo at Month 6 in patients with baselineaverage pruritus scores ≥ 4 as assessed by pruritus NRS score, a key secondary endpoint in the

RESPONSE trial (Table 3). Seladelpar led to decreased patient-reported pruritus intensity by Month 1which continued to decrease to Month 6.

Change from Baseline in ALP,

U/L (LS Mean ± SE)

Table 3. Change from Baseline in Pruritus Score at Month 6 in RESPONSE in PBC Patientswith Moderate to Severe Pruritus at Baselinea

Seladelpar Placebo Treatment10 mg (N=23) difference %(N=49) (95% CI)

Baseline average pruritus score, Mean (SD)b 6.1 (1.4) 6.6 (1.4) -

Change from baseline in pruritus score at Month 6c

Mean (SE) -3.2 (0.28) -1.7 (0.41) -1.5 (-2.5, -0.5)da Assessed using the pruritus NRS, which evaluated patients’ daily worst itching intensity on an 11-point rating scale withscores ranging from 0 (“no itching”) to 10 (“worst itching imaginable”). The pruritus NRS was administered daily in a≥ 14-day run-in period prior to randomization through Month 6. Moderate to severe pruritus was defined as a pruritus

NRS score ≥ 4.

b Baseline included mean of all daily recorded scores during the run in-period and on Day 1. The pruritus scores for eachpatient for post-baseline months were calculated by averaging the pruritus NRS scores within the scheduled week eachmonth.

c Based on LS means from a mixed-effect model for repeated measures (MMRM) for change from baseline at Months 1(Week 4), 3 (Week 12), and 6 (Week 26) accounting for baseline average pruritus score, baseline ALP level (<350 U/Lversus ALP level ≥350 U/L), treatment arm, time (in months), and treatment-by-time interaction.

d p < 0.005 for seladelpar 10 mg versus placebo.

The effect of seladelpar on pruritus was also assessed by additional patient-reported outcome measuresin RESPONSE. At Month 6, an improvement in pruritus, as observed by reductions in total scores ofthe PBC-40 Itch Domain and 5-D Itch scale, was seen with seladelpar. (Table 4).

Table 4. Change from baseline in PBC-40 Itch Domain and 5-D Itch Scale total scores at

Month 6 in RESPONSE in PBC patients with moderate to severe pruritus atbaseline

Seladelpar 10 mg Placebo Treatment difference %(N=49) (N=23) (95% CI)

PBC-40 Itch Domaina

Mean (SE) -2.2 (0.38) -0.40 (0.60) -1.8 (-3.2, -0.39)5-D Itch Scaleb

Mean (SE) -4.7 (0.53) -1.3 (0.80) -3.4 (-5.3, -1.5)a LS means were obtained using MMRM for change from baseline at Month 6 accounting for baseline PBC-40 Quality of

Life Itch Domain score, baseline ALP level (<350 U/L versus ALP level ≥350 U/L), treatment arm, time (in months), andtreatment-by-time interaction.

b LS means were obtained using MMRM for change from baseline at Month 6 accounting for baseline 5-D Itch scale,baseline ALP level (<350 U/L versus ALP level ≥350 U/L), time (in months), treatment arm, and treatment-by-timeinteraction.

The European Medicines Agency has waived the obligation to submit the results of studies withseladelpar in all subsets of the paediatric population in treatment of primary biliary cholangitis (seesection 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review any new information on this medicinal product at leastevery year and this SmPC will be updated as necessary

Following oral administration of a single dose of seladelpar 10 mg, seladelpar was readily absorbedwith median time to peak concentration (tmax) of approximately 1.5 hours.

Seladelpar exposure increased approximately dose-proportionally with single doses from 2 mg to15 mg, after which the increase in Cmax was larger than dose-proportional.

Seladelpar showed no evidence of meaningful drug accumulation after multiple daily dosing, andsteady-state was achieved from day 4 onwards after daily dosing.

Co-administration of seladelpar with food delayed the tmax by 2.5 hours relative to fasted conditionsand resulted in an approximately 32% reduction in the Cmax of seladelpar. As the overall exposure(AUC) is similar, the effects of food on seladelpar pharmacokinetics are not considered clinicallyrelevant.

In PBC patients, the steady state apparent volume of distribution of seladelpar is approximately110.3 L. Plasma protein binding of seladelpar is greater than 99%.

Seladelpar is primarily metabolized by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4. M2is a major metabolite observed in human plasma, accounting for 17.6% of the total plasmaradioactivity in the mass balance study and approximately doubling the plasma exposure compared toseladelpar. M2 is not expected to have clinically relevant pharmacological effects.

In PBC patients, the apparent oral clearance of seladelpar is 12.6 L/h. Following administration of asingle dose of 10 mg seladelpar in healthy subjects, mean elimination half-life was 6 hours forseladelpar. In PBC patients, the half-life range was 3.8 to 6.7 hours for seladelpar.

Following administration of an oral dose of radiolabelled seladelpar, 92.9% of radioactivity wasrecovered: 73.4% in urine and 19.5% in faeces. Urinary excretion of the dose as unchanged seladelparwas negligible (less than 0.01%).

Characteristics in specific groups or special populations

CYP2C9 genotype

Seladelpar is primarily metabolised in vitro by CYP2C9 which is a polymorphic enzyme. Seladelparplasma exposure (dose-normalised AUC0-inf) was 18% higher in CYP2C9 intermediate metabolisers(*1/*2, *1/*8, *1/*3, *2/*2, n=28) compared to CYP2C9 normal metabolisers (*1/*1, n=84) after asingle dose of seladelpar 1 mg to 15 mg. No conclusion could be made for poor metabolisers due toonly one identified subject with *2/*3 and no subjects with *3/*3 were identified

Age, weight, gender and race

Based on population pharmacokinetic analysis, age (19 to 79 years old), weight (45.8 to 127.5 kg),gender, and race (White, Black, Asian, other) do not have a clinically meaningful effect on thepharmacokinetics of seladelpar. No dose adjustments are warranted based on these factors.

In a dedicated clinical study of patients with mild (eGFR ≥ 60 to < 90 mL/min), moderate (eGFR ≥ 30to < 60 mL/min), and severe (< 30 mL/min and not on dialysis) renal impairment, the AUC0-inf ofseladelpar was 48%, 33% and 3% greater than in patients with normal renal function, respectively,after administration of a single 10 mg dose of seladelpar. The Cmax of seladelpar was similar in patientswith renal impairment, compared to patients with normal renal function. These differences inseladelpar AUC0-inf are not considered to be clinically meaningful. No dose adjustment of seladelpar isrequired for patients with mild, moderate, or severe renal impairment.

The pharmacokinetics of seladelpar have not been studied in patients requiring haemodialysis.

Based on a clinical pharmacology study in subjects with mild, moderate, and severe hepaticimpairment (Child-Pugh A, B, and C, respectively), seladelpar AUC was increased 1.10, 2.52, and2.12-fold, and Cmax was increased 1.33, 5.19, and 5.03-fold, respectively, compared to subjects withnormal hepatic function.

In an additional study, seladelpar exposures (Cmax, AUC) were 1.7 to 1.8-fold higher in PBC patientswith mild hepatic impairment (Child-Pugh A) with portal hypertension and 1.6 to 1.9-fold higher in

PBC patients with moderate hepatic impairment (Child-Pugh B), compared to PBC patients with mildhepatic impairment without portal hypertension, after a single oral dose of 10 mg seladelpar.

Following administration of 10 mg seladelpar once daily for 28 days in PBC patients with mild hepaticimpairment (Child-Pugh A) with portal hypertension and PBC patients with moderate hepaticimpairment (Child-Pugh B), there was no clinically meaningful accumulation of seladelpar(accumulation ratios were less than 1.2-fold).

Effect of seladelpar on other medicinal products

Seladelpar has no clinically relevant effect on the pharmacokinetics of tolbutamide(CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate),atorvastatin (CYP3A4 and OATP substrate), and rosuvastatin (BCRP and OATP substrate).

Effect of other medicinal products on seladelpar

P-gp inhibitor

In a dedicated clinical drug interaction study, seladelpar exposures were not significantly altered whena single dose of 600 mg quinidine (a P-gp inhibitor) was co-administered in healthy subjects.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproductionand development.

Seladelpar did not cause any foetal malformations or effects on embryo-foetal survival or growth inrats or rabbits. In rats, the exposure at NOAEL was 145-fold higher than the clinical AUC at therecommended dose of 10 mg, and 2-fold the clinical AUC in rabbits.

Oral administration of seladelpar at doses of 0, 5, 20 or 100 mg/kg/day in rats during gestation andlactation resulted in a dose-dependent reduction in pup body weights during the pre-weaning period atall dose levels, which was associated with slightly reduced pre-weaning survival at 100 mg/kg/day.

Growth-related delays in developmental milestones were noted (eye opening and pinna unfolding at≥ 5 mg/kg/day; hair growth and sexual maturity at 100 mg/kg/day). Growth reductions at100 mg/kg/day continued into the post-weaning maturation period and were considered adverse. Theexposure at the NOAEL of 20 mg/kg/day was 15-fold the clinical AUC.

Microcrystalline cellulose

Mannitol

Croscarmellose sodium

Butyl hydroxytoluene

Magnesium stearate

Colloidal silicon dioxide

Gelatin

Titanium dioxide

Black iron oxide (E172)

Red iron oxide (E172)

Yellow iron oxide (E172)

Indigo carmine (E132)

Black ink used to imprint “10” (on the body of the capsule shell contains)

Shellac (E904)

Propylene glycol (E1520)

Potassium hydroxide (E525)

Black iron oxide (E172)

White ink used to imprint “CBAY” (on the cap of the capsule contains)

Shellac (E904)

Propylene glycol (E1520)

Sodium hydroxide (E524)

Povidone (E1201)

Titanium dioxide

Not applicable.

4 years

Do not store above 30°C.

Lyvdelzi hard capsules are packaged in a high density polyethylene bottle closed with a polypropylenechild resistant cap containing an induction seal. Each bottle contains 30 capsules.

The following pack sizes are available: outer cartons containing 1 bottle of 30 hard capsules and outercartons containing 90 (3 bottles of 30) hard capsules. Not all pack sizes may be marketed.

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

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/24/1898/001

EU/1/24/1898/002

Date of first authorisation: 20 February 2025

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

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