WAYRILZ

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)-1 H -pyrazolo[3,4- d ]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetanyl)-1-piperazinyl]propylidene]-β-oxo-, (3 R )-. The molecular formula is C 36 H 40 FN 9 O 3 and the molecular weight is 665.77 Daltons. The chemical structural formula of rilzabrutinib is shown below: 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. Chemical Structure

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 )

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.

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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.

CYP3A Inhibitors: Avoid co-administration with moderate or strong CYP3A inhibitors. ( 7.1 ) CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers. ( 7.1 ) Gastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). WAYRILZ should be administered at least 2 hours before taking an antacid or H2 receptor antagonist. ( 7.1 ) 7.1 Effect of Other Drugs on WAYRILZ 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. 7.2 Effect of WAYRILZ on Other Drugs 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.

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.