Leaflet RHAPSIDO 25mg film-coated tablets

Rhapsido 25 mg film-coated tablets

Each film-coated tablet contains 25 mg remibrutinib.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Light yellow, round, curved film-coated tablet with a diameter of 6.7 to 7.6 mm, debossed with “LV”on one side and with the company logo on the other side.

Rhapsido is indicated for the treatment of chronic spontaneous urticaria (CSU) in adult patients withinadequate response to H1 antihistamine treatment.

Treatment should be initiated by physicians experienced in the diagnosis and treatment of chronicspontaneous urticaria.

The recommended dose of remibrutinib is 25 mg taken orally twice daily, once in the morning andonce in the evening.

If a patient misses one or more doses of remibrutinib, the patient should be instructed to take the nextdose at its regularly scheduled time. Extra doses of remibrutinib should not be taken to make up forthe missed dose or doses.

Prescribers are advised to periodically reassess the need for continued therapy. Consideration shouldbe given to discontinuing treatment in patients who have shown no response after 24 weeks oftreatment for CSU.

It is recommended to interrupt remibrutinib for 3 to 7 days before surgery and for 3 to 7 days aftersurgery depending upon the type of surgery and the risk of bleeding (see sections 4.4, 4.5 and 4.8).

No specific dose adjustment is required for elderly patients (aged ≥65 years) (see section 5.2). Limiteddata are available on the use of remibrutinib in patients older than 65 years.

No dose adjustment is required in patients with renal impairment (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment. Remibrutinib isnot recommended for use in patients with severe hepatic impairment (see section 5.2).

Rhapsido should not be used in infants and children below 6 years of age because of the unknownpotential impact on humoral immunity maturation (e.g. generation of protective immunoglobulins andmemory B cells).

The safety and efficacy of remibrutinib in children and adolescents 6 to 18 years of age have not beenestablished. No data are available.

Oral use.

Remibrutinib may be taken with or without food. Patients should be instructed to swallow the tabletwhole with water. The tablets should not be split, crushed or chewed to ensure the entire dose isdelivered correctly.

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

Risk of bleeding

Mild to moderate mucocutaneous bleeding events have occurred in patients treated with remibrutinib.

The most frequently reported events were bruising-related, such as petechiae and contusion (seesection 4.8).

Patients receiving antithrombotic agents with remibrutinib may be at an increased risk of bleeding.

The risks and benefits of co-administration of antithrombotic agents with remibrutinib must beconsidered (see section 4.5).

Patients should be instructed to seek medical advice if signs and symptoms suggestive of significantbleeding occur. If significant bleeding is suspected, treatment with remibrutinib should be interrupted.

Upon resolution, treatment may be resumed if the benefit is expected to outweigh the risk.

Interruption of remibrutinib treatment is recommended for 3 to 7 days before surgery and for 3 to7 days after surgery depending upon the type of surgery and risk of bleeding (see section 4.2).

The safety of remibrutinib with live or live-attenuated vaccines has not been studied. Vaccination withlive or live-attenuated vaccines is therefore not recommended during treatment with remibrutinib (seesection 4.5).

The safety of remibrutinib with non-live vaccines has been studied, therefore non-live vaccines can begiven during remibrutinib treatment. To optimise the immune response to non-live vaccines,interruption of remibrutinib treatment should be considered (from 1 week prior to the plannedvaccination until 2 weeks after the vaccination) (see section 4.5).

Remibrutinib is a substrate of cytochrome P450 enzyme 3A4 (CYP3A4), therefore there is a potentialfor interaction with other concomitantly administered medicinal products that are metabolised by ormodulate the activity of CYP3A4 (see section 4.5).

Concomitant use with strong CYP3A4 inhibitors increases remibrutinib exposure and consequentlymay increase the risk for adverse reactions with remibrutinib. Concomitant use with strong CYP3A4inhibitors must be avoided (see section 4.5).

Concomitant use with moderate or strong CYP3A4 inducers decreases remibrutinib exposure andconsequently may decrease the efficacy of remibrutinib. Concomitant use with moderate or strong

CYP3A4 inducers must be avoided (see section 4.5).

It is recommended to monitor patients more frequently for potential adverse reactions whenremibrutinib is used with P-glycoprotein (P-gp) substrates and breast-cancer resistance protein(BCRP) substrates with a narrow therapeutic index (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially “sodium-free”.

Remibrutinib is primarily metabolised by CYP3A4.

Active substances that may increase remibrutinib blood concentrations

Co-administration of remibrutinib with strong CYP3A4 inhibitors must be avoided. Co-administrationof ritonavir, a strong CYP3A4/P-gp inhibitor, led to a 4.3-fold increase in the AUC and a 3.3-foldincrease in the Cmax of remibrutinib.

Active substances that may decrease remibrutinib blood concentrations

Co-administration of remibrutinib with strong or moderate CYP3A4 inducers must be avoided. Co-administration of carbamazepine (strong to moderate CYP3A4 inducer) decreased the remibrutinibblood exposure by 74% (Cmax) and 78% (AUC).

Active substances whose plasma concentrations may be altered by remibrutinib

Transport substrates/inhibitors

It is recommended to monitor patients more frequently for potential adverse reactions when usingremibrutinib with P-gp and BCRP substrates with a narrow therapeutic index, especially whereminimal concentration changes can lead to adverse reactions. Co-administration of digoxin (a P-gpsubstrate with a narrow therapeutic index) with remibrutinib led to a 1.4-fold increase in the AUC anda 2.1-fold increase in the Cmax of digoxin. Co-administration of rosuvastatin (a BCRP substrate withouta narrow therapeutic index) with remibrutinib led to a 1.7-fold increase in the AUC and a 1.6-foldincrease in the Cmax of rosuvastatin.

In a drug-interaction study, the effect of administration of remibrutinib (100 mg twice daily) on thepharmacokinetics of midazolam (a sensitive CYP3A4 substrate) led to a 43% increase in the AUC anda 27% increase in the Cmax of midazolam. The effect of the clinical dose of remibrutinib (25 mg twicedaily) was not studied and may be different. Remibrutinib should not be used with concomitantadministration of CYP3A4 substrates that have narrow therapeutic indices (e.g. ciclosporin,tacrolimus, digoxin, warfarin, carbamazepine).

Co-administration of remibrutinib is not expected to have an adverse impact on the efficacy of oralcontraceptives containing ethinyloestradiol and levonorgestrel (CYP3A4 substrates) as their exposurewas not decreased in the presence of remibrutinib 100 mg twice daily (1.28- and 1.36-fold increase in

Cmax and 1.16- and 1.39-fold increase in AUC, respectively).

Effect of remibrutinib on immune response to vaccines

No data are available on the effects of live or live-attenuated vaccines in patients receivingremibrutinib and these vaccines should not be co-administered with remibrutinib (see section 4.4).

Based on a vaccination immune response study in healthy volunteers, non-live vaccines can be givenduring remibrutinib treatment. To optimise the immune response to non-live vaccines, interruption ofremibrutinib treatment should be considered (from 1 week prior to the planned vaccination until2 weeks after the vaccination).

Vaccination immune response study

In a placebo-controlled study in healthy volunteers using remibrutinib 100 mg twice daily, the immuneresponse to non-live vaccines was not significantly impacted when remibrutinib was interrupted for1 week before until 2 weeks after vaccination. However, concomitant remibrutinib treatment wasassociated with a 60% reduction of responders to the T cell-independent polysaccharide PPV23vaccine, a 21% reduction in IgG response to keyhole limpet haemocyanin (KLH) vaccine (T cell-dependent neoantigen), comparable response rates (1 to 14% reduction) for 3 out of 4 of the antigensin influenza vaccine (T cell-dependent) and a 27% reduction for 1 out of 4 of the influenza antigens.

Effect of remibrutinib on antithrombotic agents

No data are available on co-administration of remibrutinib with anticoagulants. The risks and benefitsof co-administration of antithrombotic agents with remibrutinib must be considered (see sections 4.2,4.4 and 4.8).

Interaction studies have only been performed in adults.

Sexually active women of childbearing potential must use effective contraception (methods that resultin less than 1% pregnancy rates) during remibrutinib treatment and for at least 1 week after the lastdose. Women of childbearing potential must be advised that animal studies have shown remibrutinibto be harmful to the developing foetus (see section 5.3).

There are limited data from the use of remibrutinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Rhapsido is not recommended during pregnancy.

It is unknown whether remibrutinib/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment withremibrutinib and for 1 week after the last dose.

There are no data on the effect of remibrutinib on human fertility. No adverse effects on fertility wereobserved in male and female rats (see section 5.3).

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

The most frequently reported adverse reaction is upper respiratory tract infections (14.7%) such asnasopharyngitis (6.6%) and influenza (2.5%).

Adverse reactions are listed according to MedDRA system organ class. Within each system organclass, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition,the corresponding frequency category for each adverse reaction is defined as: 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 available data).

Table 1 Adverse reactions*

System organ class Adverse reaction Frequency

Upper respiratory tract infections1 Very common

Herpes virus infections2 Common

Nervous system disorders Headache Common

Bruising Common

Petechiae Common

Contusion3 Common

Ecchymosis Common

Purpura Uncommon

Bleeding Common

Haematuria Common

Epistaxis Uncommon

Conjunctival bleeding Uncommon

Gingival bleeding Uncommon

Nausea Common

Abdominal pain Common

Musculoskeletal and

Back pain Commonconnective tissue disorders

General disorders and

Pyrexia Commonadministration site conditions

* 24-week placebo-controlled phase III studies in CSU1 Upper respiratory tract infections include preferred terms: upper respiratory tract infection, acute sinusitis,chronic sinusitis, H1N1 influenza, influenza, laryngitis, nasopharyngitis, pharyngitis, pharyngitisstreptococcal, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, tonsillitis bacterial, upper respiratory tractinfection bacterial, upper respiratory tract infection viral2 Herpes virus infections include preferred terms: herpes simplex, herpes zoster, oral herpes3 Contusion includes preferred terms: contusion, increased tendency to bruise, haematoma

The safety profile of remibrutinib in patients treated for up to 52 weeks in REMIX-1 and REMIX-2remained consistent with the adverse reactions reported in Table 1.

Mucocutaneous bleeding events

In the 24-week placebo-controlled, double-blind treatment period of the pooled dataset (REMIX-1 and

REMIX-2 phase III studies), mucocutaneous bleeding events (listed in Table 1 under “Vasculardisorders”) occurred in 7.8% of patients treated with remibrutinib. The most frequently reportedevents were bruising-related: petechiae (3.8%) and contusion (2.3%). Overall, in patients treated withremibrutinib, 92.0% of these events were mild and 8.0% were moderate in severity. The median timeto onset was 25 days and the median duration was 22 days. All cases resolved spontaneously withoutadditional treatment. No association between mucocutaneous bleeding events and low platelet countswas observed. Co-administration of remibrutinib with anticoagulants was not allowed in clinicalstudies, but co-administration with antiplatelet agents (acetylsalicylic acid (≤100 mg/day) orclopidogrel (≤75 mg/day)) was permitted (see sections 4.4 and 4.5).

In patients treated with remibrutinib, 0.5% experienced mucocutaneous bleeding events that led toremibrutinib discontinuation and 1.0% led to remibrutinib interruption (see sections 4.2, pct. 4.4 and 4.5).

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.

There was no evidence of dose-limiting adverse events seen with remibrutinib at doses up to 600 mgper day in the phase I clinical studies. Signs and symptoms of remibrutinib overdose have not beenestablished and there is no specific treatment for remibrutinib overdose.

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

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AA60

Remibrutinib is a selective Bruton’s tyrosine kinase (BTK) inhibitor that forms a covalent bond with acysteine residue in the BTK active site, leading to durable inactivation of BTK. The therapeutic effectof remibrutinib in CSU is achieved through inhibition of mast cell and basophil degranulation,including release of histamine and other proinflammatory mediators, mediated by pathogenic IgE or

IgG directed against the FcεR1 or IgE.

The effects of remibrutinib on QTc interval prolongation were predicted using concentration-QTcanalysis. The upper bound of the 90% confidence interval for the predicted mean change in QTcF wasbelow 10 msec at the expected Cmax at supratherapeutic exposures. Therefore, no clinically significantprolongation of QTcF interval is expected with therapeutic dosing of remibrutinib.

The efficacy and safety of remibrutinib were evaluated in two identical, multicentre, randomised,double-blind, placebo-controlled phase III studies (REMIX-1 and REMIX-2) in adult patients withinadequately controlled CSU despite treatment with second-generation H1 antihistamines.

In REMIX-1 and REMIX-2, patients were randomised in a 2:1 ratio to receive either remibrutinib25 mg or placebo, respectively, twice daily via the oral route for 24 weeks during the double-blindtreatment period and continued in a 28-week open-label treatment period during which all patientsreceived remibrutinib 25 mg twice daily.

REMIX-1 and REMIX-2 enrolled a total of 925 adult patients diagnosed with CSU that wasinadequately controlled despite treatment with a standard dose of a second-generation H1antihistamine as defined by the presence of itch and hives for ≥6 consecutive weeks. All patients wererequired to have a weekly urticaria activity score (UAS7) ≥16 (range 0 to 42), a weekly itch severityscore (ISS7) ≥6 (range 0 to 21) and a weekly hives severity score (HSS7) ≥6 (range 0 to 21) for 7 daysprior to randomisation. In addition to all patients receiving a stable dose of a second-generation H1antihistamine (background therapy), patients were allowed to use another second-generation H1antihistamine on an “as-needed” basis (rescue therapy) in doses up to 4-fold the standard dose.

Patients were excluded from these studies if they had evidence of clinically significant cardiovasculardisease, a significant bleeding risk, coagulation disorders, ongoing, chronic or recurrent infection,chronic or acute hepatic disease with evidence of ongoing hepatitis C or B, history of renal disease,history of gastrointestinal bleeding or history of malignancy in the last 5 years.

Demographics and baseline characteristics were generally well balanced across all groups. In REMIX-1 and REMIX-2, the median age was 45 years (range: 18-79 years) and 41 years (range: 18-81 years),with 9.6% and 7.7% ≥65 years of age and 68.3% and 65.3% female patients, respectively. Patients hada mean UAS7 of 30.28 and 29.99, a mean ISS7 of 14.59 and 14.15, and a mean HSS7 of 15.69 and15.84, respectively. At baseline, 63.4% and 59.1% of the patients had severe disease (UAS7 ≥28) and35.1% and 38.7% had moderate disease (UAS7 >16 and <28), respectively. 51.7% and 46.6% of thepatients had previous experience of angioedema in REMIX-1 and REMIX-2, respectively. 68.1% and69.2% of patients were anti-IgE biologic naive in REMIX-1 and REMIX-2, respectively. The mostcommon prior anti-IgE biologic used was omalizumab (19.5% and 19.0% in REMIX-1 and REMIX-2,respectively).

The reported mean duration of CSU at enrollment across treatment groups was 6.6 and 5.2 years in

REMIX-1 and REMIX-2, respectively, with 39.4% and 29.5% of patients having had a duration of

CSU >5 years.

The primary endpoint for the pivotal studies was:

* absolute change from baseline in UAS7 at week 12.

The secondary endpoints for the pivotal studies were:

* absolute change from baseline in ISS7 and HSS7 at week 12

* proportion of patients who achieved well-controlled disease (UAS7 ≤6) at weeks 2 and 12

* proportion of patients who achieved complete absence of itch and hives (UAS7 = 0) at week 12

* proportion of patients who achieved Dermatology Life Quality Index (DLQI) score = 0-1(yes/no) at week 12

* number of weeks with sustained disease activity control (UAS7 ≤6) up to week 12

* number of angioedema-free weeks (weekly angioedema activity score [AAS7] = 0) up toweek 12.

In both REMIX-1 and REMIX-2, the primary and all secondary endpoints were met and showedstatistically significant and clinically meaningful improvements in itch and hives symptoms in patientstreated with remibrutinib compared to patients given placebo. Results are presented in Table 2 and

Figure 1.

Table 2 Efficacy results in REMIX-1 and REMIX-2 at week 12a,b

REMIX-1 REMIX-2

Remibrutinib Placebo Remibrutinib Placebo(N=309) (N=153) (N=297) (N=153)

Change from baseline in UAS7 at week 12

LS mean (SE) CFB -20.02 (0.716) -13.79 (0.980) -19.41 (0.702) -11.73 (0.948)

LS mean (SE) CFB difference

- 6.22 (1.136) -7.68 (1.136)vs placebo95% CI for difference -8.45, -4.00 -9.91, -5.46p-value <0.001 <0.001

Change from baseline in ISS7 at week 12

LS mean (SE) CFB -9.52 (0.343) -6.89 (0.470) -8.95 (0.335) -5.72 (0.454)

LS mean (SE) CFB difference

- 2.63 (0.544) -3.23 (0.545)vs placebo95% CI for difference -3.70, -1.56 -4.29, -2.16p-value <0.001 <0.001

REMIX-1 REMIX-2

Remibrutinib Placebo Remibrutinib Placebo(N=309) (N=153) (N=297) (N=153)

Change from baseline in HSS7 at week 12

LS mean (SE) CFB -10.47 (0.401) -6.86 (0.548) -10.47 (0.394) -6.00 (0.531)

LS mean (SE) CFB difference

- 3.61 (0.635) -4.47 (0.634)vs placebo95% CI for difference -4.85, -2.36 -5.71, -3.23p-value <0.001 <0.001

Proportion of patients with UAS7 ≤6 at week 2n (%) 104 (33.7) 5 (3.3) 89 (30.0) 9 (5.9)

Treatment difference vs placebo 30.20 24.55(95% CI) 24.30, 36.10 18.31, 30.80p-value <0.001 <0.001

Proportion of patients with UAS7 ≤6 at week 12n (%) 154 (49.8) 38 (24.8) 139 (46.8) 30 (19.6)

Treatment difference vs placebo 25.44 27.61(95% CI) 16.48, 34.39 19.14, 36.08p-value <0.001 <0.001

Proportion of patients with UAS7 = 0 at week 12n (%) 96 (31.1) 16 (10.5) 83 (27.9) 10 (6.5)

Treatment difference vs placebo 20.55 21.60(95% CI) 13.35, 27.75 15.10, 28.10p-value <0.001 <0.001

Proportion of patients with DLQI = 0-1 response at week 12n (%) 120 (39.0) 34 (22.2) 106 (35.7) 28 (18.3)

Treatment difference vs placebo 17.65 18.21(95% CI) 9.14, 26.16 9.96, 26.45p-value <0.001 <0.001

Cumulative number of weeks with UAS7 ≤6 between baseline and week 12

LS mean (SE) 5.17 (0.414) 1.92 (0.241) 4.50 (0.464) 1.38 (0.216)

Rate ratio 2.69 3.26(95% CI) (2.01, 3.61) (2.26, 4.71)p-value <0.001 <0.001

Cumulative number of weeks with AAS7 = 0 between baseline and week 12

LS mean (SE) 8.43 (0.274) 6.72 (0.330) 8.81 (0.308) 6.68 (0.343)

Rate ratio 1.25 1.32(95% CI) (1.12, 1.41) (1.17, 1.49)p-value <0.001 <0.001

LS mean: Least squares mean, SE: standard error, CFB: change from baseline, CI: confidence interval, p-value: one-sided p-value, UAS7: weekly urticaria activity score, ISS7 score: weekly itch severity score, HSS7:

weekly hive severity score, DLQI: dermatology life quality index, AAS7: weekly angioedema activity score.a All endpoints with nominal one-sided p<0.001b One endpoint from week 2 (all other endpoints are from week 12)

Figure 1 Mean change from baseline in UAS7 up to week 12 in REMIX-1 and REMIX-2(observed data)

REMIX-1 REMIX-2

Weeks post baseline Weeks post baseline

Remibrutinib 25 mg b.i.d. (N=3 09) Placebo (N=153) Remibrutinib 25 mg b.i.d. (N=297) Placebo (N=153)b.i.d. = twice daily

Subgroup analyses demonstrated a consistent treatment benefit with remibrutinib over placebo acrosssubgroups including prior exposure to anti-IgE biologics and total IgE level.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Rhapsido in one or more subsets of the paediatric population in CSU (see section 4.2 for informationon paediatric use).

Remibrutinib is rapidly absorbed and reaches Cmax in the blood approximately 1 hour post-dose acrossall doses studied (0.5 mg to 600 mg). Absorption is considered to be mostly complete (86.9%). Theabsolute oral bioavailability is 33.8%.

The remibrutinib AUC increased by 33% and Cmax decreased by 5%, respectively, with a high-fat mealcompared to the fasted state following administration of remibrutinib. Remibrutinib may be taken withor without food (see section 4.2).

Remibrutinib is readily distributed to blood cells with a blood-to-plasma ratio of 0.813. Plasma proteinbinding amounts to 95.4% with no concentration dependence. Based on pooled data from populationpharmacokinetic (PopPK) analysis, the volume of distribution at steady state was 58 litres (centralcompartment) and 1 180 litres (peripheral compartment).

Remibrutinib is metabolised primarily by CYP3A4, leading to the formation of 18 inactivemetabolites, all in low amounts in circulation. Remibrutinib was the most abundant compound inblood (16.7%).

In vitro CYP metabolism is predominantly driven by CYP3A4. In vitro data showed that remibrutinibis a P-gp substrate.

Change from baseline in UAS7(Mean with standard error bar)

Change from baseline in UAS7(Mean with standard error bar)

Remibrutinib has a mean elimination half-life ranging between 1 and 2 hours at steady state. The meanapparent oral clearance at steady state (CLss/F), as determined by the PopPK analysis, is 160 litres/h.

Following intravenous administration of 100 mg [14C]-remibrutinib, excretion of radioactivity(remibrutinib and metabolites) was approximately 72.9% of the administered dose in faeces and27.1% in urine. Renal excretion of unchanged remibrutinib after oral administration was below 1% ofthe dose.

The pharmacokinetics of remibrutinib at steady state are approximately linear in the total daily doserange of 10 to 200 mg.

Clinical pharmacokinetic and pharmacodynamic (PK/PD) data estimated a BTK occupancy ≥96% inblood maintained throughout the entire day with remibrutinib 25 mg twice daily.

PopPK analysis showed that there are no clinically relevant effects of age (18 to 80 years), sex (63.5%females and 36.5% males), race/ethnicity (59.3% Non-Asian, 8.8% Mainland Chinese, 12.2%

Japanese, and 19.7% Other Asian) and body weight (39 to 162 kg; mean 74.8 kg) on the PK ofremibrutinib.

The effects of renal impairment on remibrutinib pharmacokinetics have not been evaluated in adedicated clinical study. In a PopPK analysis, no clinically meaningful relationship was observedbetween renal function tests and remibrutinib pharmacokinetics. In the PopPK analysis, there were19.3%, 2.2% and 0.1% of subjects with mild, moderate and severe renal impairment, respectively.

The Cmax and AUC of remibrutinib at steady state increased 1.85-fold and 2.15-fold in subjects withmild hepatic impairment (Child-Pugh class A), 1.65-fold and 2.07-fold in subjects with moderatehepatic impairment (Child-Pugh class B), and 1.99-fold and 3.12-fold in subjects with severe hepaticimpairment (Child-Pugh class C), respectively, relative to subjects with normal hepatic functionfollowing an oral dose of 25 mg remibrutinib twice daily. There was no change in protein binding ofremibrutinib in subjects with hepatic impairment as compared to subjects with normal hepatic function(see section 4.2).

No pharmacokinetic studies were performed with remibrutinib in patients under 18 years of age.

Remibrutinib inhibited primary antibody responses in rodent pharmacology studies and increased rattail bleeding time in haemostasis assessments. These observations, which occurred atpharmacologically and clinically relevant exposures, were considered related to effects of remibrutinibon specific B cell and platelet functions, respectively. The non-clinical data revealed no further specialhazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity,genotoxicity, carcinogenicity, and phototoxicity.

In embryo-foetal development (EFD) studies in pregnant rabbits, increased foetal externalmalformations (open/opaque eyes, small jaws, hyperflexion of forelimbs) and maternal toxicity(transiently reduced food consumption and adverse clinical signs) occurred at approximately 141 timesthe maximum recommended human dose (MRHD) of 25 mg twice daily with a no observed adverseeffect level (NOAEL)-based safety margin of 23 times the MRHD of 25 mg twice daily based on

AUC. The foetal findings were considered unlikely to be secondary to the maternal toxicity. No effecton EFD was observed in rats, with NOAEL-based safety margin of 126-fold in terms of steady-state

AUC compared to human exposure at the MRHD.

In a pre- and postnatal development (PPND) study in rats, remibrutinib induced adverse effectsaffecting maternal animals (moribundity and clinical signs of toxicity, slightly longer gestationlengths) and offspring up to lactation day 1 (slightly higher mean number of stillborn, dead or missingpups and smaller mean litter size), with NOAEL-based safety margin for maternal animals andoffspring of approximately 67 times the MRHD of 25 mg twice daily based on AUC. No adverseeffects were noted for the surviving offspring developing into adulthood.

In a fertility study in rats, remibrutinib did not impact fertility in female or male rats up to themaximum achievable exposures of 79 and 15 times higher than MRHD of 25 mg twice daily based on

AUC.

Mannitol

Microcrystalline cellulose

Copovidone

Croscarmellose sodium

Sodium stearyl fumarate

Sodium lauryl sulfate

Polyvinyl alcohol

Macrogol 4000

Talc

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Not applicable.

2 years

Store in the original package in order to protect from moisture.

Rhapsido is supplied in PA/alu/PVC/alu (polyamide/aluminium/polyvinylchloride/aluminium) blisterswith aluminium foil backing and is available in packs containing 30, 60 or 180 film-coated tablets.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/26/2024/001-003

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

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