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WAYRILZ (rilzabrutinib) is a kinase inhibitor. Rilzabrutinib is a white to off-white solid, which is freely soluble in ethanol, sparingly soluble in isopropyl alcohol and practically insoluble in water.
The chemical name for rilzabrutinib is 1-Piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetanyl)-1- piperazinyl]propylidene]-β-oxo-, (3R)-. The molecular formula is C36H 40FN 9O 3 and the molecular weight is 665.77 Daltons. The chemical structural formula of rilzabrutinib is shown below:
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Each WAYRILZ film-coated tablet for oral administration contains 400 mg rilzabrutinib. The inactive ingredients in the tablet core are crospovidone (Type A), microcrystalline cellulose, and sodium stearyl fumarate. The inactive ingredients in the tablet coating are FD&C yellow #6/Sunset yellow FCF aluminum lake, macrogol/polyethylene glycol (PEG), polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.
WAYRILZ is indicated for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.
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.
Tablets: Each 400 mg film-coated tablet is orange, capsule-shaped, and debossed with “Pâ€Â on one side and “400â€Â on the other side.
The 400 mg WAYRILZ film-coated tablets are orange, capsule-shaped, and debossed with “Pâ€Â on one side and “400â€Â on the other side.
| Package Size/Type | Content | NDC Number |
| 60-count bottle | Bottle containing 60 film-coated tablets with a child-resistant closure | 58468-0251-6 |
| 56-count carton | Carton containing 2 blister packs. Each blister pack (58468-0251-0) contains 28 film-coated tablets. | 58468-0251-5 |
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.
Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY
The following clinically important adverse reactions are described elsewhere in the labeling:
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.
Table 1: Common Adverse Reactionsa in Patients with ITP During Double-Blind Period of the LUNA-3 Study
| Adverse Reactions | WAYRILZ (N=133) | Placebo (N=69) | ||
| All Grades % | Grade 3 or Higher % | All Grades % | Grade 3 or Higher % | |
| Diarrhea | 32 | 0 | 10 | 0 |
| Nausea | 20 | 0 | 6 | 0 |
| Headache | 18 | 0 | 7 | 0 |
| Abdominal Painb | 14 | 0 | 1 | 0 |
| COVID-19 | 14 | 0.8 | 4 | 0 |
| Arthralgia | 9 | 0 | 4 | 0 |
| Dizziness | 8 | 0 | 1 | 0 |
| Nasopharyngitisb | 7 | 0 | 3 | 0 |
| Vomiting | 7 | 0 | 1 | 0 |
| Dyspepsia | 5 | 0 | 0 | 0 |
| Cougha | 5 | 0 | 0 | 0 |
| a Adverse reactions that occurred in at least 5% of WAYRILZ treated patients and at least 3% higher than placebotreated patients. b Grouped term |
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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.
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 Cmax and AUC [see Clinical Pharmacology (12.3)], which increases the risk of WAYRILZ adverse reactions.
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 Cmax and AUC [see Clinical Pharmacology (12.3)], which may reduce WAYRILZ efficacy.
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.
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.
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.
Included as part of the PRECAUTIONS section.
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)].
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.
In the event of overdosage, closely monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
No information provided.
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.
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.
The pharmacokinetics of rilzabrutinib are presented as geometric mean (% coefficient of variation) unless otherwise specified. The Cmax 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 Cmax and AUC24h are 150 ng/mL (56%) and 1540 ng.h/mL (57.5%), respectively.
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 (Tmax) is approximately 2 hours.
Effect of Food:Rilzabrutinib AUC and Cmax 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).
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.
Rilzabrutinib is predominantly metabolized by cytochrome P450 3A.
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.
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.
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 (CLCR 46 to 89 mL/min), or mild hepatic impairment (Child-Pugh class A). Rilzabrutinib exposure (both Cmax 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 CLCR <46 mL /min have not been studied.
Clinical Studies and Model-Informed Approaches Effect of Other Drugs on Rilzabrutinib
Strong CYP3A inhibitors: Concomitant use with ritonavir (strong CYP3A inhibitor) increased rilzabrutinib Cmax 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 Cmax and AUC by approximately 3-fold at steady state.
Weak CYP3A inhibitors: Cimetidine is predicted to increase rilzabrutinib Cmax by approximately 2-fold and AUC by 1.6-fold.
Strong CYP3A inducers: Coadministration of rifampin (strong CYP3A inducer) decreased rilzabrutinib Cmax and AUC by approximately 80% at steady state.
Moderate CYP3A inducers: Coadministration of moderate CYP3A inducers (efavirenz, rifabutin) is predicted to reduce rilzabrutinib Cmax and AUC by up to 70% at steady state.
Weak CYP3A inducers: Modafinil is predicted to reduce rilzabrutinib Cmax and AUC by 20%.
Proton pump inhibitor: Coadministration of esomeprazole (proton pump inhibitor) decreased rilzabrutinib Cmax 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 Cmax by 35% and AUC by 28%.
P-glycoprotein (P-gp) inhibitor: Coadministration of quinidine (P-gp inhibitor) increased rilzabrutinib Cmax 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 Cmax 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.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Instruct patients to store WAYRILZ at room temperature in the original package and to protect from light and moisture.
Instruct patients to take WAYRILZ orally twice daily at approximately the same time each day with or without food. Advise patients that WAYRILZ tablets should be swallowed whole with a glass of water, and not to cut, crush or chew the tablets [see Dosage and Administration (2.2)].
Advise patients that if they miss a dose of WAYRILZ, they should take it as soon as possible on the same day and at least 2 hours apart from the next regular scheduled dose.
Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal supplements. Advise patients to avoid eating grapefruit, starfruit, and Seville oranges and products containing these fruits with WAYRILZ [see Drug Interactions (7.1, 7.2)].
Advise patients of the possibility of serious infection, and to report any signs or symptoms [see Warnings and Precautions (5.1)] .
Inform patients that liver problems, including severe, life-threatening, or fatal hepatitis, DILI and abnormalities in liver tests, have occurred in patients treated with BTK inhibitors. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.2)].
Advise female patients of reproductive potential that WAYRILZ may cause fetal harm and to inform their healthcare providers of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with WAYRILZ and for 1 week after the last dose [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)] .
Advise women not to breastfeed during treatment with WAYRILZ and for at least 1 week after the final dose [see Use in Specific Populations (8.2)].
