RHAPSIDO- remibrutinib tablet

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RHAPSIDO- remibrutinib tablet
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]

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Overview

RHAPSIDO- remibrutinib tablet is a kinase inhibitor that is FDA approved for the treatment of chronic spontaneous urticaria (CSU) in adult patients who remain symptomatic despite H1 antihistamine treatment.. Common adverse reactions include nasopharyngitis, bleeding, headache, nausea and abdominal pain..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Chronic Spontaneous Urticaria

FDA-Labeled Indication

  • 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.

Dosing Information

  • 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).
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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of RHAPSIDO- remibrutinib tablet in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of RHAPSIDO- remibrutinib tablet in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding RHAPSIDO- remibrutinib tablet FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of RHAPSIDO- remibrutinib tablet in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of RHAPSIDO- remibrutinib tablet in pediatric patients.

Contraindications

None.

Warnings

Risk of Bleeding

  • In placebo-controlled studies in patients with CSU, mucocutaneous-related bleeding occurred in 9% of patients who received RHAPSIDO.
  • 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.
  • Use of antithrombotic agents concomitantly with RHAPSIDO may further increase the risk of bleeding.
  • Consider the benefits and risks of antithrombotic agents when used concomitantly with RHAPSIDO.
  • Monitor for signs and symptoms of bleeding.

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.

Adverse Reactions

Clinical Trials Experience

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.
  • 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 below.

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

Adverse ReactionRHAPSIDO (N = 606)
n (%)		Placebo (N = 306)
n (%)
Nasopharyngitisa67 (11%)27 (9%)
Bleedingb55 (9%)6 (2%)
Headachec41 (7%)19 (6%)
Nausea18 (3%)5 (2%)
Abdominal Paind18 (3%)6 (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.
  • 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.

Postmarketing Experience

There is limited information regarding RHAPSIDO- remibrutinib tablet Postmarketing Experience in the drug label.

Drug Interactions

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, 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, which may decrease the efficacy of RHAPSIDO.

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.

Antithrombotic Agents

  • Consider the risks and benefits of concomitant administration of antithrombotic agents with RHAPSIDO.
  • 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

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.
  • 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).


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of RHAPSIDO- remibrutinib tablet in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of RHAPSIDO- remibrutinib tablet during labor and delivery.

Nursing Mothers

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.

Pediatric Use

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet in geriatric settings.

Gender

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet with respect to specific gender populations.

Race

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet in patients with renal impairment.

Hepatic Impairment

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).

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 Cmax increased 1.85-fold in patients with mild hepatic impairment, AUC increased 2.3-fold and Cmax increased 1.65-fold in patients with moderate hepatic impairment, and AUC increased 3.49-fold and Cmax increased 1.99-fold in patients with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of RHAPSIDO- remibrutinib tablet in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of RHAPSIDO- remibrutinib tablet in patients who are immunocompromised.

Administration and Monitoring

Administration

  • 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).

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.

Monitoring

Risk of Bleeding

  • 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.
  • Consider the benefits and risks of antithrombotic agents when used concomitantly with RHAPSIDO.
  • Monitor for signs and symptoms of bleeding.

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).

IV Compatibility

There is limited information regarding the compatibility of RHAPSIDO- remibrutinib tablet and IV administrations.

Overdosage

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

Pharmacology

There is limited information regarding RHAPSIDO- remibrutinib tablet Pharmacology in the drug label.

Mechanism of Action

  • Remibrutinib is an oral, small molecule kinase inhibitor inhibiting Bruton's tyrosine kinase (BTK).
  • BTK expression occurs in mast cells, basophils, B cells, macrophages, and thrombocytes, involved in intracellular signaling via Fc epsilon receptor-1 (FcεR1), Fc gamma receptors (FcγR), and B cell antigen receptor (BCR).
  • Remibrutinib also inhibits BTK-related kinases tec protein tyrosine kinase (TEC) and BMX non-receptor tyrosine kinase (BMX), inhibiting mast cell and basophil degranulation including histamine and proinflammatory mediators.

Structure

  • RHAPSIDO (remibrutinib) is a kinase inhibitor with empirical formula C27H27F2N5O3.
  • The chemical name is: N-(3-{6-Amino-5-[2-(N-methylprop-2-enamido)ethoxy]pyrimidin-4-yl}-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, with molecular weight approximately 507.54 g/mol.
  • Remibrutinib is white to pale yellow powder, practically insoluble in water.
  • RHAPSIDO tablets are film-coated for oral administration, each containing 25 mg remibrutinib.
  • Inactive ingredients include copovidone, croscarmellose sodium, mannitol, microcrystalline cellulose, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol 4000, polyvinyl alcohol, red iron oxide (E172), talc, titanium dioxide (E171), and yellow iron oxide (E172).

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.

Pharmacokinetics

  • Following administration of remibrutinib 25 mg twice daily, the mean (standard deviation) Cmax is 57 (27) ng/mL and AUClast is 193 (136) ng*h/mL at steady state.
  • Remibrutinib Cmax 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, Cmax increases 1.6-fold and AUC0-4 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 (Tmax) 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), 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 Cmax increased 1.85-fold in patients with mild hepatic impairment, AUC increased 2.3-fold and Cmax increased 1.65-fold in patients with moderate hepatic impairment, and AUC increased 3.49-fold and Cmax increased 1.99-fold in patients with severe hepatic impairment.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

  • Strong CYP3A4 Inhibitors: With ritonavir (strong CYP3A4 inhibitor) 100 mg twice daily for 4 days, remibrutinib Cmax increased 3.3-fold and AUC increased 4.3-fold.
  • With grapefruit juice, Cmax increased 1.24-fold and AUC increased 1.3-fold.
  • Moderate CYP3A4 Inhibitors: With erythromycin (moderate CYP3A4 inhibitor) 500 mg four times daily for 7 days, remibrutinib Cmax predicted to increase approximately 1.9-fold and AUC approximately 2.3-fold.
  • Strong CYP3A4 Inducers: With carbamazepine (strong CYP3A4 inducer) 300 mg twice daily for 14 days, remibrutinib Cmax decreased 74% and AUC approximately 77%.
  • Moderate CYP3A4 Inducers: With efavirenz (moderate CYP3A4 inducer) 600 mg once daily for 14 days, remibrutinib Cmax predicted to decrease approximately 60% and AUC approximately 64%.
  • P-gp Substrates: Co-administration of remibrutinib at four times recommended dosage with 0.25 mg digoxin (P-gp substrate) increased digoxin Cmax 2.1-fold and AUC 1.4-fold.
  • BCRP Substrates: Co-administration of remibrutinib at four times recommended dosage with 10 mg rosuvastatin (BCRP and OATP1B substrate) increased rosuvastatin Cmax 1.6-fold and AUC 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.

Nonclinical Toxicology

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.

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

Baseline Demographic and Disease Characteristics

CharacteristicREMIX-1 (N=462)REMIX-2 (N=450)
Age
18-65 years, n (%)419 (91)416 (92)
>65 years, n (%)43 (9)34 (8)
Mean age, years4542
Sex, n (%)
Female313 (68)294 (65)
Race, n (%)
White or Caucasian270 (58)234 (52)
Black or African American15 (3)10 (2)
Asian139 (30)201 (45)
Ethnicity, n (%)
Hispanic/Latino116 (25)21 (5)
Disease characteristics
UAS7 ≥28, n (%)298 (65)269 (60)
Mean HSS7 score1616
Mean ISS7 score1514
Previous experience of Angioedema, n (%)240 (52)208 (46)
Previous exposure to anti-IgE biologics, n (%)147 (32)138 (31)

Efficacy Results at Week 12

EndpointREMIX-1REMIX-2
RHAPSIDO (N=309)Placebo (N=153)RHAPSIDO (N=297)Placebo (N=153)
Change from Baseline in ISS7 at Week 12
LS mean (SE) CFB-9.52 (0.34)-6.89 (0.47)-8.95 (0.34)-5.72 (0.45)
Difference in LS mean (SE) vs placebo-2.63 (0.54)—-3.23 (0.55)—
95% CI for difference-3.70, -1.56—-4.29, -2.16—
Change from Baseline in HSS7 at Week 12
LS mean (SE) CFB-10.47 (0.40)-6.86 (0.55)-10.47 (0.39)-6.00 (0.53)
Difference in LS mean (SE) vs placebo-3.61 (0.64)—-4.47 (0.64)—
95% CI for difference-4.85, -2.36—-5.71, -3.23—
Change from Baseline in UAS7 at Week 12
LS mean (SE) CFB-20.02 (0.72)-13.79 (0.98)-19.41 (0.70)-11.73 (0.95)
Difference in LS mean (SE) vs placebo-6.22 (1.14)—-7.68 (1.14)—
95% CI for difference-8.45, -4.00—-9.91, -5.46—
Proportion of Patients with UAS7 ≤6 at Week 2
n (%)104 (33.7)5 (3.3)89 (30.0)9 (5.9)
Treatment difference (95% CI)30.20 (24.30, 36.10)—24.55 (18.31, 30.80)—
Proportion of Patients with UAS7 ≤6 at Week 12
n (%)154 (49.8)38 (24.8)139 (46.8)30 (19.6)
Treatment difference (95% CI)25.44 (16.48, 34.39)—27.61 (19.14, 36.08)—
Proportion of Patients with UAS7 = 0 at Week 12
n (%)96 (31.1)16 (10.5)83 (27.9)10 (6.5)
Treatment difference (95% CI)20.55 (13.35, 27.75)—21.60 (15.10, 28.10)—
LS Mean = Least squares mean; SE = Standard error; CFB = Change from baseline; CI = Confidence interval. Multiple imputation techniques were implemented for missing data.
Mean Change from Baseline in Weekly Itch Severity Score (ISS7) and Hive Severity Score (HSS7) up to Week 24 in REMIX-2 (Observed Data)

How Supplied

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.

How Supplied

  • RHAPSIDO tablets are supplied as described in Table below.


Package ConfigurationNDC
40 mL HDPE bottle containing 60 tablets with 2 gm silica gel and a child-resistant closure0078-1483-20
2 in 1 CARTON; 30 in 1 BOTTLE0078-1483-92
30 in 1 BOTTLE0078-1483-93

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.

Images

Drug Images

Package and Label Display Panel

PRINCIPAL DISPLAY PANEL

Patient Counseling Information

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.

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.

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.

Pregnancy

  • Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to RHAPSIDO during pregnancy.

Precautions with Alcohol

Alcohol-RHAPSIDO- remibrutinib tablet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding RHAPSIDO- remibrutinib tablet Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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