Rilzabrutinib

1 INDICATIONS AND USAGE 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. WAYRILZ is a kinase inhibitor indicated for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. ( 1 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important recommendations prior to treatment. ( 2.1 , 2.3 ) Recommended dosage: 400 mg orally twice daily; swallow whole with water, with or without food. Do not cut, crush, or chew tablets. ( 2.2 ) 2.1 Recommended Testing Before Initiating WAYRILZ 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) ] . 2.2 Recommended Dosage 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. 2.3 Monitoring and Dose Modifications for Hepatotoxicity 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.

6 ADVERSE REACTIONS The following clinically important adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Hepatotoxicity, Including Drug-Induced Liver Injury [ see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 Reactions Adverse reactions that occurred in at least 5% of WAYRILZ treated patients and at least 3% higher than placebo-treated patients. 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 Pain Grouped term 14 0 1 0 COVID-19 14 0.8 4 0 Arthralgia 9 0 4 0 Dizziness 8 0 1 0 Nasopharyngitis 7 0 3 0 Vomiting 7 0 1 0 Dyspepsia 5 0 0 0 Cough 5 0 0 0 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.

12.3 Pharmacokinetics 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.