Get your patient on Wayrilz - Rilzabrutinib tablet, Film Coated (Rilzabrutinib)

Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 , 8.3) ] .

The recommended dosage of WAYRILZ is 400 mg taken orally twice daily.

WAYRILZ can be taken at approximately the same time each day with or without food. In patients who experience gastrointestinal symptoms, taking WAYRILZ with food may improve tolerability. Advise patients to swallow tablets whole with a glass of water. Advise patients not to cut, crush or chew the tablets.

If a dose is missed, patients should take the missed dose of WAYRILZ as soon as possible on the same day and at least 2 hours apart from the next regular scheduled dose.

If taking antacid or histamine H2 receptor antagonist, administer the dose of WAYRILZ at least 2 hours before the antacid or histamine H2 receptor antagonist.

Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment with WAYRILZ. For patients who develop abnormal liver tests after WAYRILZ, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If Drug-Induced Liver Injury (DILI) is suspected, withhold WAYRILZ. Upon confirmation of DILI, discontinue WAYRILZ.

Risk Summary

Based on animal data, WAYRILZ may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of rilzabrutinib to pregnant rats and rabbits during organogenesis at exposures 4- to 10-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 400 mg twice daily did not cause adverse developmental effects. However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22-times the human exposure (based on AUC) at the MRHD ( see Data ). There are no available clinical data on the use of WAYRILZ during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and 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

Rilzabrutinib given to pregnant rats by oral gavage at 50, 150 or 300 mg/kg/day during the period of organogenesis (gestation day 7 to 17) did not cause adverse effects on embryo-fetal development at exposures approximately 10-times the clinical exposure at the maximum recommended human dose (MRHD), based on AUC. Increased incidence of post-implantation loss (25%), delayed ossification associated with a markedly lower (24%) mean fetal weight, and increased skeletal (scoliosis) and visceral malformations (abnormalities of major vessels, urogenital tract, and kidney) occurred in a preliminary study in rats at a maternally toxic dose of 500 mg/kg/day that resulted in exposures 22-times the clinical exposure at the MRHD, based on AUC.

Rilzabrutinib given to pregnant rabbits by oral gavage at 10, 30 or 100 mg/kg/day during the period of organogenesis (gestation day 7 to 19) did not cause adverse effects on embryo-fetal development at exposures approximately 4-times the clinical exposures at the MRHD, based on AUC. Renal visceral malformations occurred in a single fetus in a preliminary study in rabbits at 150 mg/kg/day that resulted in exposures 5.6-times the clinical exposure at the MRHD, based on AUC.

In a pre- and postnatal developmental toxicity study, pregnant rats were given rilzabrutinib by oral gavage at doses of 50, 150 or 300 mg/kg/day during the periods of gestation, parturition, and lactation (gestation day 7 to lactation day 21). Decreased body weight was observed in pups in the presence of maternal toxicity at 300 mg/kg/day, at exposures approximately 18-times the MRHD based on AUC. There were no effects of rilzabrutinib on the ability of F1 offspring to reproduce or on subsequent F2 development at any dose.

Risk Summary

There are no data on the presence of rilzabrutinib or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Due to the potential for adverse reactions in a breastfed child from WAYRILZ, advise lactating women not to breastfeed while taking WAYRILZ and for at least 1 week after the final dose.

Based on preliminary animal data, WAYRILZ may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] .

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during WAYRILZ treatment and for 1 week after stopping treatment.

Safety and effectiveness of WAYRILZ have not been established in pediatric patients.

Of the 202 patients in the LUNA-3 study [see Clinical Studies (14) ] , 36 (18%) patients were 65 years of age and older, and 9 (5%) patients were 75 years of age and older. No overall differences in safety and efficacy were observed between patients 65 years of age and older and younger adult patients.

Avoid administration of WAYRILZ in patients with moderate or severe hepatic impairment (Child-Pugh class B-C) because of potential for increased rilzabrutinib exposures. Dose modification is not required for patients with mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology (12.3) ] .

Avoid use in patients with severe renal impairment. Patients with severe renal impairment were not studied. Dose modification is not required for patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) ] .

An increased risk of serious infections (including bacterial, viral, or fungal) can occur in patients treated with Bruton's tyrosine kinase (BTK) inhibitors, including WAYRILZ. In the LUNA-3 trial, fatal pneumonia occurred in one participant in the WAYRILZ group. Other serious infections [one each (0.8%)] included COVID-19 infection, wound infection, and one patient experienced urinary tract infection and kidney abscess. Monitor patients for signs and symptoms of infection and treat appropriately.

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, can occur in patients treated with BTK inhibitors. In the clinical trials of WAYRILZ in patients with ITP, elevations of liver transaminases occurred and were generally mild to moderate in severity. Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment with WAYRILZ. For patients who develop abnormal liver tests after WAYRILZ, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold WAYRILZ. Upon confirmation of DILI, discontinue WAYRILZ.

Based on findings from preliminary animal reproduction studies, WAYRILZ may cause fetal harm when administered to a pregnant woman. Adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22-times the human exposure [based on area under the curve (AUC)] at the maximum recommended human dose (MRHD), and renal visceral malformations occurred in a single rabbit fetus at 5.6-times the human exposure (based on AUC) at the MRHD. Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ treatment. Advise females of reproductive potential to use an effective method of contraception during treatment with WAYRILZ and for 1 week after the final dose [see Use in Specific Populations (8.1 , 8.3) ] .

Because clinical trials are conducted under widely varying conditions, adverse reaction 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 WAYRILZ was evaluated in a randomized, double-blind (DB), placebo-controlled, parallel-group study (LUNA-3), in which 202 adult patients with persistent or chronic ITP received either WAYRILZ (n=133) or placebo (n=69) [see Clinical Studies (14) ] .

During the 24-week DB period, the median duration of WAYRILZ exposure was 98 days (range: 22 to 182).

The most common adverse reactions (≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19. Adverse reactions resulting in discontinuation of WAYRILZ included erythema nodosum, neutropenia, arthralgia, dyspepsia, headache, pain in extremity, abdominal discomfort, diarrhea, nausea, and pneumonia and occurred in 4.5% of patients.

Table 1 presents common adverse reactions from the LUNA-3 Study.

Specific Adverse Reactions

Gastrointestinal Events

In the LUNA-3 Study DB period, the most common gastrointestinal (GI) adverse reactions were diarrhea (32%), nausea (20%), and abdominal pain (14%) in the WAYRILZ group. These events were Grade 1 or 2. Of those who experienced GI adverse reactions, 2 patients discontinued due to GI adverse reactions. Recovery or resolution with supportive treatment allowing continuation of WAYRILZ treatment occurred in 91% of patients with diarrhea, 85% with nausea and 79% with abdominal pain.

Neutropenia

In the LUNA-3 Study DB period, Grade 1 or 2 neutropenia occurred in 11% of patients in the WAYRILZ group.

Strong and Moderate CYP3A Inhibitors

Avoid concomitant use of WAYRILZ with strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor cannot be avoided, and these inhibitors will be used short term (such as anti-infectives for seven days or less), interrupt treatment with WAYRILZ. Avoid concomitant use of grapefruit, starfruit and products containing these fruits, and Seville oranges with WAYRILZ, as these are moderate and strong inhibitors of CYP3A.

Rilzabrutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases rilzabrutinib C _max and AUC [see Clinical Pharmacology (12.3) ] , which increases the risk of WAYRILZ adverse reactions.

Strong and Moderate CYP3A Inducers

Avoid concomitant use of WAYRILZ with strong or moderate CYP3A inducers.

Rilzabrutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inducer decreases rilzabrutinib C _max and AUC [see Clinical Pharmacology (12.3) ] , which may reduce WAYRILZ efficacy.

Gastric Acid Reducing Agents

Administer the dose of WAYRILZ at least 2 hours before administration of an antacid or histamine H2 receptor antagonist. Avoid concomitant use of proton pump inhibitors with WAYRILZ.

Rilzabrutinib exhibits pH-dependent solubility. Acid reducing agents decrease rilzabrutinib exposure [see Clinical Pharmacology (12.3) ] , which may reduce WAYRILZ efficacy.

CYP3A Substrates

Monitor for adverse reactions of the concurrently administered CYP3A substrate more frequently and consider dosage adjustment in accordance with the Prescribing Information of the CYP3A substrate.

Rilzabrutinib is a moderate inhibitor of CYP3A and increases exposure of these substrates [see Clinical Pharmacology (12.3) ] , which increases the risk of adverse reactions related to these substrates.

P-gp, BCRP, and OATP1B Substrates

Monitor for adverse reactions of the concurrently administered P-gp, BCRP, or OATP1B substrate more frequently, unless otherwise recommended in the substrate Prescribing Information, when WAYRILZ is used concomitantly with P-gp, BCRP, or OATP1B substrates where minimal substrate concentration changes may lead to serious adverse reactions.

Rilzabrutinib is an inhibitor of P-gp, BCRP and OATP1B in vitro . The effect of concomitant use of WAYRILZ with OATP1B and BCRP substrates has not been established in clinical studies. However, based on in vitro inhibitory potential [see Clinical Pharmacology (12.3) ] , concomitant use of WAYRILZ may increase the risk of adverse reactions related to these substrates.

Rilzabrutinib is a small-molecule, covalent, reversible kinase inhibitor targeting Bruton's tyrosine kinase (BTK). Rilzabrutinib mediates its therapeutic effect in ITP through immune modulation including 1) inhibition of B cell activation, and 2) interruption of antibody-coated cell phagocytosis by Fcγ receptor (FcγR) in spleen and liver. In vitro , rilzabrutinib reduced autoantibody signaling mediated through the FcγR pathway, blocked B cell signaling, and decreased autoantibody generation through effects on B cell activation.

Plasma Exposure and BTK Occupancy

WAYRILZ has a short duration of systemic exposure with a long duration of action on the target due to its slow dissociation from BTK. At therapeutic doses in healthy participants, durable BTK occupancy in peripheral blood mononuclear cells was observed over a 24-hour period.

Cardiac Electrophysiology

In a Thorough QT study, concentration dependent shortening in the QTc interval was observed. Following a single dose of rilzabrutinib 400 mg, the mean maximum QTcF decrease of -7 msec (90% confidence interval: -9 msec to -5 msec) was observed at 2 hours post-dose. The mean maximum QTcF decrease at exposures 4-fold the highest recommended dose, i.e., 400 mg BID, was -10 msec (90% confidence interval: -12 msec to -8 msec) at 2 hours post-dose.

The pharmacokinetics of rilzabrutinib are presented as geometric mean (% coefficient of variation) unless otherwise specified. The C _max and AUC of rilzabrutinib increase proportionally following administration of multiple doses of 300 mg to 600 mg. Steady-state plasma levels are reached within 3 days with accumulation up to 1.3-fold at the approved recommended dosage. Following daily doses of 400 mg rilzabrutinib twice daily, the steady-state C _max and AUC24h are 150 ng/mL (56%) and 1540 ng.h/mL (57.5%), respectively.

Absorption

The absolute oral bioavailability of rilzabrutinib is 4.7%. Following a single oral dose of 400 mg rilzabrutinib, the median time to peak plasma concentration (T _max ) is approximately 2 hours.

Effect of Food:

Rilzabrutinib AUC and C _max decreased by 20% and 31%, respectively, following administration of a single oral 400 mg dose with a high fat meal (approximately 1,000 calories with 50% of total caloric content from fat).

Distribution

The volume of distribution at terminal phase (Vz) after IV administration is 149L. Rilzabrutinib is 97.5% bound to plasma proteins and the blood-to-plasma ratio is 0.786.

Metabolism

Rilzabrutinib is predominantly metabolized by cytochrome P450 3A.

Elimination

The clearance of rilzabrutinib is time-independent. Following multiple doses of 400 mg twice daily rilzabrutinib in patients with ITP, mean CL/F ranged from 246 to 911 L/h. Based on the population pharmacokinetic analysis in patients with ITP, the mean CL/F was 516 L/h.

In Phase 1 studies, the half-life of rilzabrutinib ranged between 1.6 to 4.5 hours.

Excretion

Following administration of a single 400 mg 14C-labeled rilzabrutinib dose in healthy subjects, approximately 86% of the dose was recovered in feces (9% unchanged) and to a lesser extent in urine (~5%) and bile (~6%). Approximately 0.03% of rilzabrutinib was excreted unchanged in the urine.

Special Populations

No clinically significant differences in the pharmacokinetics of rilzabrutinib were observed based on age (12 to 80 years), sex, race, mild to moderate renal impairment (CL _CR 46 to 89 mL/min), or mild hepatic impairment (Child-Pugh class A). Rilzabrutinib exposure (both C _max and AUC) increased by approximately 4.5-fold in participants with moderate hepatic impairment (Child-Pugh class B). Patients with severe hepatic impairment (Child-Pugh class C) and CL _CR <46 mL/min have not been studied.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Other Drugs on Rilzabrutinib

Strong CYP3A inhibitors : Concomitant use with ritonavir (strong CYP3A inhibitor) increased rilzabrutinib C _max by approximately 5-fold and AUC by 8-fold at steady state.

Moderate CYP3A inhibitors : Concomitant use with moderate CYP3A inhibitors (fluconazole, erythromycin and verapamil) is predicted to increase rilzabrutinib C _max and AUC by approximately 3-fold at steady state.

Weak CYP3A inhibitors : Cimetidine is predicted to increase rilzabrutinib C _max by approximately 2-fold and AUC by 1.6-fold.

Strong CYP3A inducers : Coadministration of rifampin (strong CYP3A inducer) decreased rilzabrutinib C _max and AUC by approximately 80% at steady state.

Moderate CYP3A inducers : Coadministration of moderate CYP3A inducers (efavirenz, rifabutin) is predicted to reduce rilzabrutinib C _max and AUC by up to 70% at steady state.

Weak CYP3A inducers : Modafinil is predicted to reduce rilzabrutinib C _max and AUC by 20%.

Proton pump inhibitor : Coadministration of esomeprazole (proton pump inhibitor) decreased rilzabrutinib C _max by 55% and AUC by 51%.

H2 receptor antagonist : Administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib C _max by 35% and AUC by 28%.

P-glycoprotein (P-gp) inhibitor : Coadministration of quinidine (P-gp inhibitor) increased rilzabrutinib C _max and AUC by approximately 13% at steady state.

Effect of Rilzabrutinib on Other Drugs

CYP3A4 substrates : Concomitant use of a single dose of rilzabrutinib 400 mg with midazolam (sensitive CYP3A inhibitor) increased midazolam C _max and AUC by 2.2-fold as observed in study with healthy participants. Midazolam AUC is predicted to increase up to 3.0-fold in patients with immune thrombocytopenia following coadministration with 400 mg rilzabrutinib twice daily.

In Vitro Studies

CYP Enzymes : Rilzabrutinib is a substrate of CYP3A. Rilzabrutinib is both an inhibitor and inducer of CYP3A.

Transporters : Rilzabrutinib is a substrate of P-gp and BCRP, but not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP. Rilzabrutinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, and BSEP at clinically relevant concentrations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors. The non-carcinogenic dose was the highest dose tested of 100 mg/kg/day for males and 50 mg/kg/day for females.

Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.

In a fertility study in male and female rats, rilzabrutinib was administered for a minimum of 28 days (males) and 15 days (females) prior to cohabitation and continued through gestation day 7 at doses of 50, 150 or 300 mg/kg/day by oral gavage. Rilzabrutinib had no effect on mating, estrous cycle, fertility, sperm parameters, or any ovarian and uterine parameters at any dose.

Storage

Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store and dispense in the original package. Protect from light and moisture.