FDA Label for Rhapsido

1     Indications And Usage

RHAPSIDO^® is indicated for the treatment of chronic spontaneous urticaria (CSU) in adult patients who remain symptomatic despite H1 antihistamine treatment.

Limitations of Use:

RHAPSIDO is not indicated for other forms of urticaria.

2.1     Recommended Dosage

The recommended dosage is 25 mg taken orally twice daily with or without food.

• Swallow RHAPSIDO tablet whole with water. Do not split, crush, or chew RHAPSIDO.

Missed Dose(s)

If a dose or doses of RHAPSIDO is missed, skip the missed dose, and take the next dose at its regularly scheduled time. Do not take an extra dose(s) of RHAPSIDO to make up for a missed dose(s).

2.2     Temporary Interruption Of Rhapsido For Surgery

Interrupt treatment with RHAPSIDO for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding [see Warnings and Precautions (5.1), Adverse Reactions (6.1) and Drug Interactions (7.2)].

3     Dosage Forms And Strengths

Tablets: 25 mg, light yellow, round, curved, unscored, film-coated tablet, debossed with “LV” on one side and Novartis logo on the other side. The tablet diameter is 7 mm.

4     Contraindications

None.

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.

6.1     Clinical Trials Experience

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.

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.

8.1     Pregnancy

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).

8.2     Lactation

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.

8.4     Pediatric Use

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

8.5     Geriatric Use

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.

8.6     Hepatic Impairment

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)].

10     Overdosage

Consider contacting the poison help line (1-800-222-1222) or a medical toxicologist for overdose management recommendations.

11     Description

RHAPSIDO (remibrutinib) is a kinase inhibitor.

Its empirical formula (remibrutinib) is C₂₇H₂₇F₂N₅O₃. The chemical name for remibrutinib is N-(3-{6-Amino-5-[2-(N-methylprop-2-enamido)ethoxy]pyrimidin-4-yl}-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Its molecular weight is approximately 507.54 g/mol. The chemical structure of remibrutinib is:

chemical structure of remibrutinib - rhapsido 01

Remibrutinib is white to pale yellow powder, and it is practically insoluble in water.

RHAPSIDO is supplied as film-coated tablets for oral administration, with each film-coated tablet containing 25 mg of remibrutinib. The tablet core inactive ingredients are copovidone, croscarmellose sodium, mannitol, microcrystalline cellulose, sodium lauryl sulfate, and sodium stearyl fumarate. The tablet coating inactive ingredients are polyethylene glycol 4000, polyvinyl alcohol, red iron oxide (E172), talc, titanium dioxide (E171), and yellow iron oxide (E172).

12.1     Mechanism Of Action

Remibrutinib is an oral, small molecule kinase inhibitor that inhibits Bruton’s tyrosine kinase (BTK). BTK is an intracellular protein expressed in mast cells, basophils, B cells, macrophages, and thrombocytes. BTK is involved in intracellular signaling via Fc epsilon receptor-1 (FcεR1), Fc gamma receptors (FcγR), and the B cell antigen receptor (BCR). Remibrutinib also inhibits the BTK-related kinases tec protein tyrosine kinase (TEC) and BMX non-receptor tyrosine kinase (BMX).

Remibrutinib inhibits 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.

12.2     Pharmacodynamics

Exposure-Response

Within the range from 0.2 to 4 times the daily recommended dose, a flat dose-response relationship was observed for the weekly urticaria activity score (UAS7) at Week 4.

Cardiac Electrophysiology

At concentrations approximately 9 times the mean steady state peak plasma concentrations provided by the recommended dose, clinically significant QTc prolongation was not observed.

Effects on Blood Pressure

The effect of remibrutinib treatment on blood pressure was assessed in CSU patients using a 24-hour blood pressure measurement by ambulatory blood pressure monitoring (ABPM) at steady state (Week 4) compared to baseline in a multi-center, open-label study (A2305). The study enrolled 144 patients with CSU inadequately controlled by H1 antihistamines, who were administered remibrutinib 25 mg twice daily. Remibrutinib 25 mg twice daily was not associated with clinically significant changes in blood pressure.

12.3     Pharmacokinetics

Following administration of remibrutinib 25 mg twice daily, the mean (standard deviation) C_max is 57 (27) ng/mL and AUC_last is 193 (136) ng*h/mL at steady state. Remibrutinib C_max and AUC increase in a dose-proportional manner between 0.4 to 4 times the recommended dosage. Following administration of multiple doses of 25 mg twice daily, C_max increases 1.6-fold and AUC_0-4 increases 2.7-fold.

No clinically significant differences in remibrutinib pharmacokinetics were observed between healthy subjects and patients with CSU.

Absorption

Remibrutinib median (min, max) time to maximum plasma concentration (T_max) is 1 hour (0, 4 hours) at steady state.

Effect of food

No clinically significant differences in remibrutinib pharmacokinetics were observed following administration of a high-fat meal (1000 calories, 50% fat).

Distribution

Remibrutinib blood-to-plasma ratio is 0.813 in vitro. Plasma protein binding is 95.4% and is not concentration-dependent in vitro. The estimated remibrutinib steady state apparent (oral) volume of distribution is 1238 L.

Elimination

Remibrutinib estimated elimination half-life is 1 to 2 hours with an apparent (oral) clearance of 160 L/hr.

Metabolism

Remibrutinib is primarily metabolized by CYP3A4.

Excretion

Following IV administration of ¹⁴C remibrutinib to healthy subjects, 70% of the total radioactivity was recovered in feces (0% as unchanged remibrutinib), and 30% was recovered in urine (2.9% as unchanged remibrutinib).

Specific Populations

No clinically significant differences in the pharmacokinetics of remibrutinib were observed based on age (range: 18 to 80 years), sex (63.5% females and 36.5% males), race/ethnicity (59.3% Non-Asian [White, Black, and Others], 8.8% Mainland Chinese, 12.2% Japanese, and 19.7% other Asian), body weight (range: 39 to 162 kg), and mild (eGFR 60-89 mL/min/1.73 m², estimated by Cockcroft-Gault), moderate (eGFR 30-59 mL/min/1.73 m²) or severe (eGFR 15-29 mL/min/1.73 m²) renal impairment.

Patients with Hepatic Impairment

The pharmacokinetics of remibrutinib were evaluated in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment following administration of 25 mg twice daily. Relative to patients with normal hepatic function, remibrutinib AUC increased 2.33-fold and C_max increased 1.85-fold in patients with mild hepatic impairment, AUC increased 2.3-fold and C_max increased 1.65-fold in patients with moderate hepatic impairment, and AUC increased 3.49-fold and C_max increased 1.99-fold in patients with severe hepatic impairment [see Use in Special Populations (8.6)].

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A4 Inhibitors: Remibrutinib C_max increased by 3.3-fold and AUC increased by 4.3-fold following concomitant administration with ritonavir (a strong CYP3A4 inhibitor) 100 mg twice daily for 4 days [see Drug Interactions (7.1)].

Remibrutinib C_max increased by 1.24-fold and AUC increased by 1.3-fold when co-administered with grapefruit juice.

Moderate CYP3A4 Inhibitors: Remibrutinib C_max is predicted to increase by approximately 1.9-fold and AUC is predicted to increase by approximately 2.3-fold following concomitant administration with erythromycin (a moderate CYP3A4 inhibitor) 500 mg four times a day for 7 days [see Drug Interactions (7.1)].

Strong CYP3A4 Inducers: Remibrutinib C_max decreased by 74% and AUC decreased by approximately 77% following concomitant administration with carbamazepine (a strong CYP3A4 inducer) 300 mg twice daily for 14 days [see Drug Interactions (7.1)].

Moderate CYP3A4 Inducers: Remibrutinib C_max is predicted to decrease by approximately 60% and AUC is predicted to decrease by approximately 64% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days [see Drug Interactions (7.1)].

P-gp Substrates: Co-administration of remibrutinib at four times the recommended dosage with a single dose of 0.25 mg digoxin (a P-gp substrate) increased digoxin C_max by 2.1-fold and AUC by 1.4-fold [see Drug Interactions (7.1)].

BCRP Substrates: Co-administration of remibrutinib at four times the recommended dosage with a single dose of 10 mg rosuvastatin (a BCRP and OATP1B substrate) increased rosuvastatin C_max by 1.6-fold and AUC by 1.7-fold.

Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with remibrutinib: oral midazolam (CYP3A4 substrate), oral contraceptives containing ethinyl estradiol and levonorgestrel (CYP3A4 substrate), tolbutamide (CYP2C9 substrate), caffeine (CYP1A2 substrate), and coproporphyrin I (an endogenous OATP1B substrate).

In Vitro Studies

CYP450 Enzymes: Remibrutinib is a CYP3A4 substrate. Remibrutinib inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5. Remibrutinib induces CYP1A2, CYP2B6, CYP2C9 and CYP3A4/5.

Transporter Systems: In vitro, remibrutinib is a P-gp substrate. Remibrutinib inhibits P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2 and MATE1.

13.1     Carcinogenesis, Mutagenesis, Impairment Of Fertility

Remibrutinib did not show evidence of carcinogenic potential in a 6-month rasH2 mouse study at oral doses up to 1500 mg/kg/day and a 2-year rat carcinogenicity study at oral doses up to 300 mg/kg/day (approximately 8 times and 98 times than MRHD of 25 mg twice daily based on AUC for males and females, respectively).

Remibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay and was not clastogenic in an in vitro micronucleus assay in human peripheral lymphocytes or in an in vivo blood reticulocyte micronucleus assay in rats.

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.

14     Clinical Studies

The efficacy of RHAPSIDO for chronic spontaneous urticaria (CSU) in adult patients who remain symptomatic despite H1 antihistamine treatment was evaluated in two identical, 52-week, multi-center, randomized, double-blind, placebo-controlled clinical trials (REMIX-1 [NCT05030311] and REMIX-2 [NCT05032157]).

REMIX-1 and REMIX-2 enrolled a total of 925 adult patients, diagnosed with CSU inadequately controlled despite treatment with H1 antihistamines, 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 0-42), a weekly itch severity score (ISS7) ≥6 (range 0-21) and a weekly hives severity score (HSS7) ≥6 (range 0-21) for 7 days prior to randomization. Patients were randomized in a 2:1 ratio to receive either RHAPSIDO 25 mg or placebo, respectively, orally twice daily for 24 weeks during the double-blind treatment period and subsequently continued in a 28-week open-label treatment period, during which all patients received RHAPSIDO 25 mg twice daily. While REMIX-1 and REMIX-2 clinical trials included an open-label period, efficacy is based on results from 912 patients treated during the controlled period of 24 weeks.

Demographics and baseline characteristics in REMIX-1 and REMIX-2 are provided in Table 2.

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% and 29% of the patients having a duration of CSU > 5 years.

The co-primary endpoints were absolute change from baseline in ISS7 and HSS7 at Week 12. The ISS7 (range 0 to 21) was defined as the sum of the daily itch severity scores (range 0 to 3) recorded over a 7-day period. The HSS7 (range 0 to 21) was defined as the sum of the daily hive severity scores (range 0 to 3) recorded over a 7-day period. The key secondary endpoint was absolute change from baseline in UAS7 at Week 12. The UAS7 (range 0 to 42) was a composite of the ISS7 and HSS7.

Secondary endpoints included proportion of patients who achieved UAS7 ≤6 at Weeks 2 and 12, and the proportion of patients who achieved complete absence of itch and hives (UAS7 = 0) at Week 12. In both REMIX-1 and REMIX-2 studies, the co-primary and all secondary endpoints showed statistically significant improvement in itch and hives symptoms in patients treated with RHAPSIDO compared to patients treated with placebo. Results are presented in Table 3.

Figure 1 shows the effect of RHAPSIDO over time up to Week 24 in REMIX-2 patients treated with RHAPSIDO. The results were similar in REMIX-1.

Figure 1 Mean Change from Baseline in Weekly Itch Severity Score (ISS7) and Hive Severity Score (HSS7) up to Week 24 in REMIX-2 (Observed Data)

Figure 1 Mean Change from Baseline in Weekly Itch Severity Score (ISS7) and Hive Severity Score (HSS7) up to Week 24 in REMIX-2 (Observed Data) - rhapsido 02

Improvements in ISS7 and HSS7 at Week 12 were consistent regardless of patients’ baseline total IgE level.

16     How Supplied/Storage And Handling

RHAPSIDO tablets are supplied as described in Table 4:

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense and store in the original container in order to protect from moisture.

17     Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Patient Information).

Administration Instructions:

Inform patients to take RHAPSIDO with or without food. Advise patients not to split, crush, or chew the tablet and to swallow the tablet whole with water [see Dosage and Administration (2.1)].

Risk of Bleeding:

Inform patients that bleeding can occur with the use of RHAPSIDO, and to report any signs and symptoms to their healthcare practitioner. Inform patients that RHAPSIDO should be interrupted for 3 to 7 days for any surgical procedures. Instruct patients to inform their healthcare practitioner if they use RHAPSIDO with antithrombotic agents due to the potential increased risk of bleeding [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Live Attenuated Vaccines:

Instruct patients to inform the healthcare practitioner that they are taking RHAPSIDO prior to any potential vaccinations. Advise patients that the vaccines containing live virus (live and live-attenuated) should not be given during treatment with RHAPSIDO [see Warnings and Precautions (5.2)].

Pregnancy:

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to RHAPSIDO during pregnancy [see Use in Specific Populations (8.1)].

Distributed by:
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, New Jersey 07936

© Novartis

T2025-55

Principal Display Panel

NDC 0078-1483-20

Rhapsido^®

(remibrutinib) tablets

25 mg per tablet

Swallow tablets whole with water.

Do not split, crush, or chew tablets.

Rx only

60 tablets

NOVARTIS

PRINCIPAL DISPLAY PANEL NDC 0078-1483-20 Rhapsido® (remibrutinib) tablets 25 mg per tablet Swallow tablets whole with water. Do not split, crush, or chew tablets. Rx only 60 Tablets NOVARTIS - rhapsido 03