WAYRILZ

5 WARNINGS AND PRECAUTIONS Serious Infections: Monitor patients for signs and symptoms of infection, evaluate promptly, and treat. ( 5.1 ) Hepatotoxicity, Including Drug-Induced Liver Injury: Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment. ( 5.2 ) Embryo-Fetal Toxicity: Based on preliminary animal data, WAYRILZ may cause fetal harm. Advise females of reproductive potential of the potential risk and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Serious Infections 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. 5.2 Hepatotoxicity, Including Drug-Induced Liver Injury 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. 5.3 Embryo-Fetal Toxicity 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) ] .

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.

<table width="80%"><caption>Table 1: Common Adverse Reactions<footnote ID="fna">Adverse reactions that occurred in at least 5% of WAYRILZ treated patients and at least 3% higher than placebo-treated patients.</footnote> in Patients with ITP During Double-Blind Period of the LUNA-3 Study </caption><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule" colspan="2">WAYRILZ (N=133)</th><th styleCode="Rrule" colspan="2">Placebo (N=69)</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grade 3 or Higher %</th><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grade 3 or Higher %</th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">32</td><td styleCode="Rrule">0</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Abdominal Pain<footnote ID="fnb">Grouped term</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">COVID-19</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nasopharyngitis<footnoteRef IDREF="fnb"/></td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Cough<footnoteRef IDREF="fna"/></td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr></tbody></table>