Get your patient on Rhapsido - Remibrutinib tablet (Remibrutinib)

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).

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)] .

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)] .

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.

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.

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)] .

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.

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.

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.

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.

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 ¹⁴ C 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 m ² , estimated by Cockcroft-Gault), moderate (eGFR 30-59 mL/min/1.73 m ² ) or severe (eGFR 15-29 mL/min/1.73 m ² ) 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.

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.