RHAPSIDO Film-coated tablet Ref.[116081] Active ingredients: Remibrutinib

5.1 Risk of Bleeding

In placebo-controlled studies in patients with CSU, mucocutaneous-related bleeding occurred in 9% of patients who received RHAPSIDO [see Adverse Reactions (6.1)]. Interrupt treatment with RHAPSIDO if bleeding is observed and resume if the benefit is expected to outweigh the risk.

Interrupt treatment with RHAPSIDO for 3 to 7 days pre- and post-surgery or invasive procedures [see Dosage and Administration (2.2)].

Use of antithrombotic agents concomitantly with RHAPSIDO may further increase the risk of bleeding [see Drug Interactions (7.2)]. Consider the benefits and risks of antithrombotic agents when used concomitantly with RHAPSIDO. Monitor for signs and symptoms of bleeding.

5.2 Live Attenuated Vaccines

No data are available on the effects of live or live-attenuated vaccines in patients receiving RHAPSIDO. The use of live and live-attenuated vaccines should be avoided in patients receiving RHAPSIDO.

Because clinical trials are conducted under widely varying conditions, adverse drug reaction (ADR) rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of RHAPSIDO was based on a pooled safety population from two identical clinical trials of 52 weeks duration, REMIX-1 and REMIX-2 [see Clinical Studies (14)]. The pooled safety population consisted of 912 adult patients with CSU who remain symptomatic despite H1 antihistamine treatment and who received RHAPSIDO 25 mg orally twice daily (N=606) or placebo (N=306) for 24 weeks during the double-blind, controlled treatment period of the trial.

Adverse reactions that occurred at an incidence greater than or equal to 3% and more common than the placebo group from the pooled safety population (REMIX-1 and REMIX-2) during the 24-week blinded, placebo-controlled treatment period are shown in Table 1.

Table 1. Adverse Reactions with RHAPSIDO with Incidence ≥3% and More Common than Placebo in Adult Patients with CSU (REMIX-1 and REMIX-2):

^a includes acute sinusitis, chronic sinusitis, nasopharyngitis, pharyngitis, pharyngitis streptococcal, rhinitis, rhinitis allergic, and upper respiratory tract infection
^b includes conjunctival bleeding, contusion, ecchymosis, epistaxis, gingival bleeding, hematoma, hematuria, hemorrhagic ovarian cyst, intermenstrual bleeding, petechiae, purpura, and urinary occult blood
^c includes headache and migraine
^d includes abdominal discomfort, abdominal distention, abdominal pain and abdominal pain upper

Specific Adverse Reactions

Bleeding

In the pooled safety population (REMIX-1 and REMIX-2), bleeding occurred in 9% of patients treated with RHAPSIDO compared to 2% in the placebo group during the 24-week controlled treatment period [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Drug Interactions (7.2)]. Petechiae (4%) and contusion (2%) were the most commonly reported reactions in patients treated with RHAPSIDO. No severe bleeding reactions occurred. No association between bleeding reactions and low platelet counts was observed. In patients treated with RHAPSIDO, 0.5% experienced bleeding reactions that led to RHAPSIDO discontinuation, while none of these reactions occurred in the placebo group. Similar safety findings were observed through Week 52 [see Clinical Studies (14)].

7.1 Effect of Other Drugs on RHAPSIDO

Strong or Moderate CYP3A4 Inhibitors

Avoid use of RHAPSIDO with strong or moderate CYP3A4 inhibitors.

Remibrutinib is a CYP3A4 substrate. Concomitant use with a strong or moderate CYP3A4 inhibitor increases remibrutinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of RHAPSIDO adverse reactions.

Strong or Moderate CYP3A4 Inducers

Avoid use of RHAPSIDO with strong or moderate CYP3A4 inducers.

Remibrutinib is a CYP3A4 substrate. Concomitant use with a strong or moderate CYP3A4 inducer decreases remibrutinib exposure [see Clinical Pharmacology (12.3)], which may decrease the efficacy of RHAPSIDO.

7.2 Effect of RHAPSIDO on Other Drugs

P-gp Substrates

Monitor more frequently for adverse reactions when using RHAPSIDO with P-glycoprotein (P-gp) substrates where minimal concentration changes may lead to serious adverse reactions (e.g., digoxin).

Remibrutinib is a P-gp inhibitor. Remibrutinib increases exposure of P-gp substrates, which may increase the risk of adverse reactions related to P-gp substrates [see Clinical Pharmacology (12.3)].

Antithrombotic Agents

Consider the risks and benefits of concomitant administration of antithrombotic agents with RHAPSIDO [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

No data are available on concomitant use of RHAPSIDO with anticoagulants. The concomitant use of RHAPSIDO and anticoagulants was not allowed in clinical studies. Use of the antiplatelet agents, acetyl salicylic acid at doses up to 100 mg daily or clopidogrel up to 75 mg daily, was allowed in the RHAPSIDO clinical studies.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RHAPSIDO during pregnancy. Pregnant women exposed to RHAPSIDO and healthcare providers are encouraged to contact Novartis Pharmaceuticals Corporation at 1-888-669-6682.

Risk Summary

Available data on the use of RHAPSIDO during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of remibrutinib to pregnant rabbits during organogenesis at exposures 141-times the human exposure at the maximum recommended human dose (MRHD) of 25 mg twice daily based on area under the curve (AUC) resulted in adverse developmental outcomes including external malformations. No adverse developmental effects were observed with oral administration of remibrutinib to pregnant rats during organogenesis at exposures up to 126-times the human exposure at the MRHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development (EFD) study in pregnant rabbits, remibrutinib was administered orally at doses of 100, 300, and 450 mg/kg/day during the period of organogenesis. Increased fetal external malformations (e.g. open/opaque eyes, small jaws, hyperflexion of forelimbs) and maternal toxicity (transiently reduced food consumption and adverse clinical signs) occurred at 300 mg/kg/day (141-times the MRHD based on AUC). The fetal findings were considered unlikely to be secondary to the maternal toxicity. The dose of 450 mg/kg/day was not tolerated by the pregnant rabbits.

In an EFD study in pregnant rats, remibrutinib was administered orally at doses of 100, 300, and 1000 mg/kg/day during the period of organogenesis. Remibrutinib did not cause adverse effects to the fetus at exposures up to 126 times that at the MRHD based on AUC.

In a pre- and postnatal development (PPND) study, remibrutinib was administered orally to pregnant rats at doses of 100, 300, and 1000 mg/kg/day from gestation day 6 to lactation day (LD) 21. Remibrutinib induced adverse effects at 1000 mg/kg/day (approximately 194 times the MRHD based on body surface area [BSA]), affected maternal animals (moribundity and clinical signs of toxicity, slightly longer gestation lengths) and offspring up to LD1 (slightly higher mean number of stillborn, dead, or missing pups, and smaller mean litter size). No adverse effects at doses up to 1000 mg/kg/day were noted in the surviving offspring developing into adulthood. No effects were observed at 300 mg/kg/day (approximately 58 times the MRHD based on BSA).

Risk Summary

No data are available regarding the presence of remibrutinib in either human or animal milk, its effects on the breastfed child, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RHAPSIDO and any potential adverse effects on the breastfed child from RHAPSIDO or from the underlying maternal condition.

The safety and effectiveness of RHAPSIDO have not been established in pediatric patients.

Of the total number of patients treated with RHAPSIDO in clinical studies for CSU, 53 (8.7%) were 65 to 85 years of age, with no patients over 85 years of age [see Clinical Studies (14)]. There were no observed differences in safety and/or effectiveness in geriatric patients compared to younger adult patients.

RHAPSIDO exposure is increased in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C) relative to patients with normal hepatic function. Avoid use of RHAPSIDO in patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) [see Clinical Pharmacology (12.3)].