Rhapsido · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-100804 · has-adverse-reaction-information · PDF-Seite 6

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). 6 Table 1 Adverse reactions* System organ class Adverse reaction Frequency Upper respiratory tract infections1 Very common Infections and infestations Herpes virus infections2 Common Nervous system disorders Headache Common Bruising Common Petechiae Common Contusion3 Common Ecchymosis Common Purpura Uncommon Vascular disorders Bleeding Common Haematuria Common Epistaxis Uncommon Conjunctival bleeding Uncommon Gingival bleeding Uncommon Nausea Common Gastrointestinal disorders Abdominal pain Common Musculoskeletal and Back pain Common connective tissue disorders General disorders and

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HOS-100800 · has-contraindication-information · PDF-Seite 3

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

HOS-100799 · has-indication-information · PDF-Seite 2

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

HOS-100802 · has-interaction-information · PDF-Seite 4

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 Cmax 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% (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 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 Cmax 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 Cmax of rosuvastatin. 4 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 Cmax 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 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

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HOS-100803 · has-pregnancy-information · PDF-Seite 5

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. 5 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).

HOS-100801 · has-warning-information · PDF-Seite 3

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). 3 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 breas

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