Rhapsido 25 mg Film-coated Tablet

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

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

Posology

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

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

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

Dose interruption

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

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. Remibrutinib is not recommended for use in patients with severe hepatic impairment (see section 5.2).

Paediatric population

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

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

Method of administration

Oral use.

Remibrutinib may be taken with or without food. Patients should be instructed to swallow the tablet whole with water. The tablets should not be split, crushed or chewed to ensure the entire dose is delivered 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 (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 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% (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^*

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA60

Mechanism of action

Remibrutinib is a selective Bruton's tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to durable inactivation of BTK. The therapeutic effect of 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.

Pharmacodynamic effects

Cardiac electrophysiology

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

Clinical efficacy and safety

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 with inadequately 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 remibrutinib 25 mg or placebo, respectively, twice daily via the oral route for 24 weeks during the double-blind treatment period and continued in a 28-week open-label treatment period during which all patients received remibrutinib 25 mg twice daily.

REMIX-1 and REMIX-2 enrolled a total of 925 adult patients diagnosed with CSU that was inadequately controlled despite treatment with a standard dose of a second-generation H1 antihistamine as defined by the presence of itch and hives for ≥6 consecutive weeks. All patients were required to have a weekly urticaria activity score (UAS7) ≥16 (range 0 to 42), a weekly itch severity score (ISS7) ≥6 (range 0 to 21) and a weekly hives severity score (HSS7) ≥6 (range 0 to 21) for 7 days prior to randomisation. In addition to all patients receiving a stable dose of a second-generation H1 antihistamine (background therapy), patients were allowed to use another second-generation H1 antihistamine 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 cardiovascular disease, 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 had a mean UAS7 of 30.28 and 29.99, a mean ISS7 of 14.59 and 14.15, and a mean HSS7 of 15.69 and 15.84, respectively. At baseline, 63.4% and 59.1% of the patients had severe disease (UAS7 ≥28) and 35.1% and 38.7% had moderate disease (UAS7 >16 and <28), respectively. 51.7% and 46.6% of the patients had previous experience of angioedema in REMIX-1 and REMIX-2, respectively. 68.1% and 69.2% of patients were anti-IgE biologic naive in REMIX-1 and REMIX-2, respectively. The most common 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 to week 12.

Clinical response

In both REMIX-1 and REMIX-2, the primary and all secondary endpoints were met and showed statistically significant and clinically meaningful improvements in itch and hives symptoms in patients treated 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 12^a,b

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

b.i.d. = twice daily

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

Paediatric population

The Medicines and Healthcare products Regulatory 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 information on paediatric use).

Absorption

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

Effect of food

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

Distribution

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

Biotransformation

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

In vitro studies

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

Elimination

Remibrutinib has a mean elimination half-life ranging between 1 and 2 hours at steady state. The mean apparent 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 and 27.1% in urine. Renal excretion of unchanged remibrutinib after oral administration was below 1% of the dose.

Linearity/non-linearity

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

Pharmacokinetic/pharmacodynamic relationship(s)

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

Special populations

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 of remibrutinib.

Renal impairment

The effects of renal impairment on remibrutinib pharmacokinetics have not been evaluated in a dedicated clinical study. In a PopPK analysis, no clinically meaningful relationship was observed between renal function tests and remibrutinib pharmacokinetics. In the PopPK analysis, there were 19.3%, 2.2% and 0.1% of subjects with mild, moderate and severe renal impairment, respectively.

Hepatic impairment

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

Paediatric population

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 rat tail bleeding time in haemostasis assessments. These observations, which occurred at pharmacologically and clinically relevant exposures, were considered related to effects of remibrutinib on specific B cell and platelet functions, respectively. The non-clinical data revealed no further special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and phototoxicity.

Reproductive toxicity

In embryo-foetal development (EFD) studies in pregnant rabbits, increased foetal external malformations (open/opaque eyes, small jaws, hyperflexion of forelimbs) and maternal toxicity (transiently reduced food consumption and adverse clinical signs) occurred at approximately 141 times the maximum recommended human dose (MRHD) of 25 mg twice daily with a no observed adverse effect 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 effect on 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 effects affecting maternal animals (moribundity and clinical signs of toxicity, slightly longer gestation lengths) and offspring up to lactation day 1 (slightly higher mean number of stillborn, dead or missing pups and smaller mean litter size), with NOAEL-based safety margin for maternal animals and offspring of approximately 67 times the MRHD of 25 mg twice daily based on AUC. No adverse effects 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 the maximum achievable exposures of 79 and 15 times higher than MRHD of 25 mg twice daily based on AUC.

Tablet core

Mannitol

Microcrystalline cellulose

Copovidone

Croscarmellose sodium

Sodium stearyl fumarate

Sodium lauryl sulfate

Tablet coating

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) blisters with 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 local requirements.