RHAPSIDO Film-coated tablet Ref.[116560] Active ingredients: Remibrutinib

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 (see section 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 be considered (see section 4.5).

Patients should be instructed to seek medical advice if signs and symptoms suggestive of significant bleeding 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 to 7 days after surgery depending upon the type of surgery and risk of bleeding (see section 4.2).

Vaccinations

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

The safety of remibrutinib with non-live vaccines has been studied, therefore non-live vaccines can be given 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 planned vaccination until 2 weeks after the vaccination) (see section 4.5).

Interactions

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

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

Concomitant use with moderate or strong CYP3A4 inducers decreases remibrutinib exposure and consequently 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 when remibrutinib is used with P-glycoprotein (P-gp) substrates and breast-cancer resistance protein (BCRP) substrates with a narrow therapeutic index (see section 4.5).

Excipient with known effect

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

Remibrutinib is primarily metabolised by CYP3A4.

Active substances that may increase remibrutinib blood concentrations

CYP3A4 inhibitors

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

Active substances that may decrease remibrutinib blood concentrations

CYP3A4 inducers

Co-administration of remibrutinib with strong or moderate CYP3A4 inducers must be avoided. Co-administration of carbamazepine (strong to moderate CYP3A4 inducer) decreased the remibrutinib blood exposure by 74% (C_max) 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 using remibrutinib with P-gp and BCRP substrates with a narrow therapeutic index, especially where minimal concentration changes can lead to adverse reactions. Co-administration of digoxin (a P-gp substrate with a narrow therapeutic index) with remibrutinib led to a 1.4-fold increase in the AUC and a 2.1-fold increase in the C_max of digoxin. Co-administration of rosuvastatin (a BCRP substrate without a narrow therapeutic index) with remibrutinib led to a 1.7-fold increase in the AUC and a 1.6-fold increase in the C_max of rosuvastatin.

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

Oral contraceptives

Co-administration of remibrutinib is not expected to have an adverse impact on the efficacy of oral contraceptives containing ethinyloestradiol and levonorgestrel (CYP3A4 substrates) as their exposure was not decreased in the presence of remibrutinib 100 mg twice daily (1.28- and 1.36-fold increase in C_max 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 receiving remibrutinib 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 given 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 planned vaccination until 2 weeks after the vaccination).

Vaccination immune response study

In a placebo-controlled study in healthy volunteers using remibrutinib 100 mg twice daily, the immune response to non-live vaccines was not significantly impacted when remibrutinib was interrupted for 1 week before until 2 weeks after vaccination. However, concomitant remibrutinib treatment was associated with a 60% reduction of responders to the T cell-independent polysaccharide PPV23 vaccine, 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 antigens in 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 benefits of co-administration of antithrombotic agents with remibrutinib must be considered (see sections 4.2, 4.4 and 4.8).

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential

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

Pregnancy

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions are listed according to MedDRA system organ class. Within each system organ class, 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*:

^* 24-week placebo-controlled phase III studies in CSU
¹ Upper respiratory tract infections include preferred terms: upper respiratory tract infection, acute sinusitis, chronic sinusitis, H1N1 influenza, influenza, laryngitis, nasopharyngitis, pharyngitis, pharyngitis streptococcal, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, tonsillitis bacterial, upper respiratory tract infection bacterial, upper respiratory tract infection viral
² Herpes virus infections include preferred terms: herpes simplex, herpes zoster, oral herpes
³ 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-2 remained consistent with the adverse reactions reported in Table 1.

Description of selected adverse reactions

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 "Vascular disorders") occurred in 7.8% of patients treated with remibrutinib. The most frequently reported events were bruising-related: petechiae (3.8%) and contusion (2.3%). Overall, in patients treated with remibrutinib, 92.0% of these events were mild and 8.0% were moderate in severity. The median time to onset was 25 days and the median duration was 22 days. All cases resolved spontaneously without additional treatment. No association between mucocutaneous bleeding events and low platelet counts was observed. Co-administration of remibrutinib with anticoagulants was not allowed in clinical studies, but co-administration with antiplatelet agents (acetylsalicylic acid (≤100 mg/day) or clopidogrel (≤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 to remibrutinib discontinuation and 1.0% led to remibrutinib interruption (see sections 4.2, 4.4 and 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.