<?xml version="1.0" encoding="UTF-8"?><section ID="ID_411ecced-cfea-451d-b533-987a2068e927">
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<code code="34084-4" codeSystem="2.16.840.1.113883.6.1" displayName="ADVERSE REACTIONS SECTION"/>
<title>6 ADVERSE REACTIONS </title>
<text>
<paragraph>The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>Serious and Opportunistic Infections <content styleCode="italics">[see </content>
<content styleCode="italics">
<content styleCode="underline">
<linkHtml href="#ID_a4c950e2-42fd-447e-9d4a-ea48d372a53f">Warnings and Precautions (5.1)</linkHtml>
</content>
</content>
<content styleCode="italics">]</content>
</item>
<item>
<caption>•</caption>Hemorrhage <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_76c626fd-a938-4c7d-a620-957d6afcaca7">Warnings and Precautions (5.2)</linkHtml>
</content>]</content>
</item>
<item>
<caption>•</caption>Cytopenias <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_cf4be055-4786-457c-8934-4b05fafa7114">Warnings and Precautions (5.3)</linkHtml>
</content>]</content>
</item>
<item>
<caption>•</caption>Second Primary Malignancies <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">Warnings and Precautions (5.4)</linkHtml>
</content>]</content>
</item>
<item>
<caption>•</caption>Cardiac Arrhythmias <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_b13613ac-a265-4264-9e98-65d552d22e92">Warnings and Precautions (5.5)</linkHtml>
</content>]</content>
</item>
<item>
<caption>•</caption>Hepatotoxicity, including DILI <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_cc286d4e-e97d-4ab0-be03-9c2b33ed674f">Warnings and Precautions (5.6)</linkHtml>
</content>]</content>
</item>
</list>
</text>
<effectiveTime value="20250116"/>
<excerpt>
<highlight>
<text>
<paragraph>Most common adverse reactions (incidence ≥ 30%) were: anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. <linkHtml href="#ID_81dc654f-96ff-4182-a11c-59a3a4d5515e">(6.1)</linkHtml>
</paragraph>
<paragraph>
<content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or <linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml>
</content>
</paragraph>
</text>
</highlight>
</excerpt>
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<section ID="ID_81dc654f-96ff-4182-a11c-59a3a4d5515e">
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>6.1 Clinical Trials Experience </title>
<text>
<paragraph>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.</paragraph>
<paragraph>The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 1,764 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 1,256 patients in 9 trials, and CALQUENCE combinations in 508 patients in 3 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 80% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1,764 patients, excluding laboratory abnormalities, were diarrhea (37%), upper respiratory tract infection (36%), headache (35%), musculoskeletal pain (33%), lower respiratory tract infection (32%), and fatigue (32%). The most common grade 3 or 4 laboratory abnormalities (≥10%) were absolute neutrophil count decreased (31%), absolute lymphocyte count decreased (23%), platelets decreased (11%), and hemoglobin decreased (10%).</paragraph>
<paragraph>Previously Untreated Mantle Cell Lymphoma</paragraph>
<paragraph>The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without BR) in patients with MCL [see <linkHtml href="#ID_fe66f622-c188-465c-b212-b5eaa4c4a2f4">Clinical Studies (14.1)</linkHtml>].</paragraph>
<paragraph>ECHO</paragraph>
<paragraph>The safety of CALQUENCE in combination with bendamustine and rituximab (CALQUENCE plus BR) was evaluated in 297 patients with previously untreated MCL in ECHO [see <linkHtml href="#ID_fe66f622-c188-465c-b212-b5eaa4c4a2f4">Clinical Studies (14.1)</linkHtml>]. The trial enrolled patients with previously untreated MCL, ≥ 65 years of age with no intention for transplant, total bilirubin ≤ 1.5 × ULN, AST or ALT ≤ 2.5 × ULN, and estimated creatinine clearance of > 50 mL/min. Patients received 6 cycles (as 28-day cycles) of CALQUENCE 100 mg orally twice daily (n = 297) or placebo (n = 297) in combination with bendamustine and rituximab. Patients then received CALQUENCE 100 mg orally twice daily or placebo continuously until progressive disease or unacceptable toxicity, with 12 additional dosages of rituximab every other cycle up to Cycle 30.</paragraph>
<paragraph>The median duration of treatment with CALQUENCE was 28.6 months. A total of 171 (57.6%) patients were treated with CALQUENCE for ˃ 24 months and 122 (41.1%) patients were treated for ˃ 36 months.</paragraph>
<paragraph>Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR. Serious adverse reactions reported in ≥ 2% of patients were pneumonia (23%; includes COVID-19 pneumonia), COVID-19 (20%; includes COVID-19 pneumonia), pyrexia (6%), second primary malignancy (7%), rash (3.4%), febrile neutropenia (3.4%), atrial fibrillation (3%), sepsis (2.7%), and anemia (2.4%). Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including COVID-19 (6%; includes COVID-19 pneumonia), pneumonia (1%), sepsis (0.3%), second primary malignancy (0.7%), and pneumonitis (0.3%).</paragraph>
<paragraph>Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in > 10% included infections, cytopenias, rashes, and gastrointestinal toxicity. Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥ 4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia.</paragraph>
<paragraph>Table 4 and Table 5 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO.</paragraph>
<table styleCode="Noautorules" width="100%">
<caption>Table 4: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO</caption>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<tbody>
<tr>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Body Systems</content>
</paragraph>
<paragraph>
<content styleCode="bold">Adverse Reactions*</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">CALQUENCE plus BR</content>
</paragraph>
<paragraph>
<content styleCode="bold">N = 297</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo plus BR </content>
</paragraph>
<paragraph>
<content styleCode="bold"> N = 297</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold"> (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade</content>
</paragraph>
<paragraph>
<content styleCode="bold"> 3 or 4 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Grades</content>
</paragraph>
<paragraph>
<content styleCode="bold"> (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade</content>
</paragraph>
<paragraph>
<content styleCode="bold"> 3 or 4 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin and subcutaneous tissue disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Rash<sup>a</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>47</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Infections</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Covid-19<sup>b</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>38</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Upper respiratory</paragraph>
<paragraph> tract infection<sup>c</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>….Pneumonia<sup>d</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal disorder</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Diarrhea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>28</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Vomiting</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Constipation</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">General disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Fatigue</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Pyrexia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Edema</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Nervous system disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Headache</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Dizziness</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Cough</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Dyspnea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.7</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Neoplasms</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Secondary primary</paragraph>
<paragraph> malignancy<sup>e</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Musculoskeletal and connective tissue disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Arthralgia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Vascular disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Hemorrhage<sup>f</sup>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<sup>*</sup>Excludes laboratory terms.</paragraph>
<paragraph>
<sup>a</sup> Includes rash, dermatitis, and other related terms.</paragraph>
<paragraph>
<sup>b</sup> Includes the following fatal adverse reactions: n=24 for COVID-19.</paragraph>
<paragraph>
<sup>c</sup> Includes upper respiratory tract infection, sinusitis, pharyngitis, and related terms.</paragraph>
<paragraph>
<sup>d</sup> Includes pneumonia, terms containing pneumonia, and related infections. COVID-19 pneumonia is represented under both Pneumonia and COVID-19.</paragraph>
<paragraph>
<sup>e</sup> Includes terms related to malignant neoplasms including cutaneous neoplasms.</paragraph>
<paragraph>
<sup>f</sup> Includes all terms containing hematoma or hemorrhage and related terms indicative of bleeding.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus BR included bruising, abdominal pain, atrial fibrillation or flutter, and tumor lysis syndrome.</paragraph>
<table styleCode="Noautorules" width="100%">
<caption>Table 5: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO</caption>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Laboratory Abnormality</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">CALQUENCE plus BR<sup>a</sup>
</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo plus BR<sup>a</sup>
</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All grade </content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade</content>
</paragraph>
<paragraph>
<content styleCode="bold"> 3 or 4 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All grade </content>
</paragraph>
<paragraph>
<content styleCode="bold">(%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade</content>
</paragraph>
<paragraph>
<content styleCode="bold"> 3 or 4 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hematologic Abnormalities</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Lymphocytes decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>98</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>87</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>97</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>89</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hemoglobin decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>80</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>65</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Neutrophils decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>76</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>56</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>77</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>51</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Platelets decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>69</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>60</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Chemistry Abnormalities</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>AST increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>53</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>50</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Uric acid increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>45</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>45</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>ALT increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>41</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Potassium increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>38</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Creatinine increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>28</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Phosphate decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>4.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Potassium decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Bilirubin increased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<sup>a</sup> The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with a baseline value and at least one post-treatment value.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Grade 4 laboratory abnormalities in > 15% of patients treated with CALQUENCE plus BR include absolute lymphocyte count decreased (26%), absolute neutrophil count decreased (36%), and uric acid increased (17%).</paragraph>
<paragraph>Previously Treated Mantle Cell Lymphoma</paragraph>
<paragraph>ACE-LY-004</paragraph>
<paragraph>The safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every 12 hours) in 124 patients with previously treated MCL in Trial LY-004 <content styleCode="italics">[see <linkHtml href="#ID_fe66f622-c188-465c-b212-b5eaa4c4a2f4">Clinical Studies (14.2)</linkHtml>]</content>. The median duration of treatment with CALQUENCE was 16.6 (range: 0.1 to 26.6) months. A total of 91 (73.4%) patients were treated with CALQUENCE for ≥ 6 months and 74 (59.7%) patients were treated for ≥ 1 year.</paragraph>
<paragraph>The most common adverse reactions (≥ 20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 1 severity for the non-hematologic, most common events were as follows: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea.</paragraph>
<paragraph>Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.</paragraph>
<paragraph>Tables 6 and 7 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.</paragraph>
<table width="100%">
<caption>Table 6: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004</caption>
<col width="34%"/>
<col width="34%"/>
<col width="33%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Body System</content>
</paragraph>
<paragraph>
<content styleCode="bold">Adverse Reactions</content>
<footnote ID="_Ref483993900">Per NCI CTCAE version 4.03.</footnote>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">CALQUENCE Monotherapy</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=124</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">All Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Nervous system disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Headache</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.6</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Gastrointestinal disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diarrhea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>3.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nausea</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>19</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Abdominal pain</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Constipation</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Vomiting</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.6</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">General disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Fatigue</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>28</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.8</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Musculoskeletal and connective tissue disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Myalgia</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.8</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Skin and subcutaneous tissue disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Bruising<footnote ID="_Ref25046307">Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rash<footnote ID="_Ref25046322">Rash: Includes all terms containing ‘rash’</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.8</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Vascular disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hemorrhage<footnote ID="_Ref25046344">Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.8</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Epistaxis</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>6</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-</paragraph>
</td>
</tr>
</tbody>
</table>
<table ID="_RefID0EEYAE" width="100%">
<caption>Table 7: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004</caption>
<col width="37%"/>
<col width="37%"/>
<col width="27%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Hematologic</content>
</paragraph>
<paragraph>
<content styleCode="bold">Adverse Reactions</content>
<footnote ID="_Ref495334911">Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.</footnote>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">CALQUENCE Monotherapy</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=124</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">All Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Hemoglobin decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>46</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Platelets decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Neutrophils decreased</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>15</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.</paragraph>
<paragraph>
<content styleCode="bold">
<content styleCode="underline">Chronic Lymphocytic Leukemia</content>
</content>
</paragraph>
<paragraph>The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials <content styleCode="italics">[see Clinical Studies (14.3)]</content>.</paragraph>
<paragraph>The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.</paragraph>
<paragraph>
<content styleCode="italics">ELEVATE-TN</content>
</paragraph>
<paragraph>The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL <content styleCode="italics">[see <content styleCode="underline">
<linkHtml href="#ID_fe66f622-c188-465c-b212-b5eaa4c4a2f4">Clinical Studies (14.2)</linkHtml>
</content>]</content>.</paragraph>
<paragraph>The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea. </paragraph>
<paragraph>ELEVATE-TN</paragraph>
<paragraph>The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL [see Clinical Studies (14.3)].</paragraph>
<paragraph>Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity. Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6 cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every 12 hours until disease progression or unacceptable toxicity. The trial required age ≥ 65 years of age or 18 to < 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases ≤ 3 times ULN and total bilirubin ≤ 1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. </paragraph>
<paragraph>During randomized treatment, the median duration of exposure to CALQUENCE in the CALQUENCE+G and CALQUENCE monotherapy arms was 27.7 months (range 0.3 to 40 months), with 95% and 92% and 89% and 86% of patients with at least 6 months and 12 months of exposure, respectively. In the obinutuzumab and chlorambucil arm the median number of cycles was 6 with 84% of patients receiving at least 6 cycles of obinutuzumab, 70% of patients received at least 6 cycles of chlorambucil. Eighty-five percent of patients in the CALQUENCE+G arm received at least 6 cycles of obinutuzumab. </paragraph>
<paragraph>In the CALQUENCE+G and CALQUENCE monotherapy arms, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE+G arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (2.8% to 7%).</paragraph>
<paragraph>In the CALQUENCE+G arm, adverse reactions led to treatment discontinuation in 11% of patients and a dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse reactions led to discontinuation in 10% and dose reduction in 4% of patients. </paragraph>
<paragraph>Tables 8 and 9 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial. </paragraph>
<table cellpadding="0pt" width="100%">
<caption>Table 8: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN)</caption>
<col width="25%"/>
<col width="23%"/>
<col width="10%"/>
<col width="10%"/>
<col width="10%"/>
<col width="10%"/>
<col width="10%"/>
<tbody>
<tr>
<td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Body System</content>
</paragraph>
<paragraph>
<content styleCode="bold">Adverse Reaction</content>
<footnote ID="_Ref25056882">Per NCI CTCAE version 4.03</footnote>
</paragraph>
<paragraph>
<content styleCode="bold"> </content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">CALQUENCE plus Obinutuzumab</content>
<br/>
<content styleCode="bold">N=178</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">CALQUENCE Monotherapy</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=179</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Obinutuzumab plus Chlorambucil </content>
<br/>
<content styleCode="bold">N=169</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="bottom">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Infections</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Infection<footnote ID="_Ref25075994">Includes any adverse reactions involving infection or febrile neutropenia</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>69</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>22<footnote ID="_Ref25056915">Includes 3 fatal cases in the CALQUENCE plus obinutuzumab arm, 3 fatal cases in the CALQUENCE monotherapy arm and 1 fatal case in the obinutuzumab plus chlorambucil arm</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>65</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>14<footnoteRef IDREF="_Ref25056915"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>46</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>13<footnoteRef IDREF="_Ref25056915"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Upper respiratory tract infection<footnote ID="_Ref25077433">Upper respiratory tract infection, nasopharyngitis and sinusitis</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>35</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Lower respiratory tract infection<footnote ID="_Ref25244953">Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>4.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Urinary tract infection</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="bottom">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Blood and lymphatic system disorders</content>
<footnote ID="_Ref25244976">Derived from adverse reactions and laboratory data</footnote>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Neutropenia<footnote ID="_Ref24457582">Includes neutropenia, neutrophil count decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>53</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>78</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>50</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Anemia<footnote ID="_Ref24457689">Includes anemia, red blood cell count decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>52</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>53</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>54</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Thrombocytopenia<footnote ID="_Ref24457839">Includes thrombocytopenia, platelet count decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>51</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>3.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>61</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Lymphocytosis<footnote ID="_Ref24457470">Includes lymphocytosis, lymphocyte count increased, and related laboratory data</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Nervous system disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Headache</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Dizziness</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Gastrointestinal disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Diarrhea</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>4.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>35</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>21</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Nausea</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Musculoskeletal and connective tissue disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Musculoskeletal pain<footnote ID="_Ref25059801">Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>32</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Arthralgia</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>4.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.2</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">General disorders and administration site conditions</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Fatigue<footnote ID="_Ref25059814">Includes asthenia, fatigue, and lethargy</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>34</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.2</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Skin and subcutaneous tissue disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Bruising<footnote ID="_Ref24458251">Includes bruise, contusion, and ecchymosis</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>31</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>21</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>5</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Rash<footnote ID="_Ref25059837">Includes rash, dermatitis, and other related terms</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>26</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.2</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>25</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0.6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>9</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0.6</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Vascular disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Hemorrhage<footnote ID="_Ref25059852">Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis</footnote>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>1.7</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>1.7</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>6</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>
<content styleCode="italics">Neoplasms:</content> second primary malignancy (10%), non-melanoma skin cancer (5%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Cardiac disorders:</content> atrial fibrillation or flutter (3.6%), hypertension (5%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Infection:</content> herpesvirus infection (6%)</item>
</list>
<table ID="_RefID0EC2AG" cellpadding="0pt" width="100%">
<caption>Table 9: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)</caption>
<col width="21%"/>
<col width="21%"/>
<col width="12%"/>
<col width="12%"/>
<col width="12%"/>
<col width="12%"/>
<col width="12%"/>
<thead>
<tr>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref25060203">Per NCI CTCAE version 4.03</footnote>
<footnote ID="_Ref25060238">Excludes electrolytes</footnote>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">CALQUENCE plus Obinutuzumab</content>
<br/>
<content styleCode="bold">N=178</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">CALQUENCE Monotherapy</content>
<br/>
<content styleCode="bold">N=179</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Obinutuzumab plus Chlorambucil</content>
<br/>
<content styleCode="bold">N=169</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Uric acid increase</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>29</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>37</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>37</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">ALT increase</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>30</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>20</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>6</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">AST increase</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>38</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>60</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>8</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>
<content styleCode="bold">Bilirubin increase</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="middle">
<paragraph>0.6</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.</paragraph>
<paragraph>
<content styleCode="italics">ASCEND</content>
</paragraph>
<paragraph>The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized, open-label study (ASCEND) [see Clinical Studies (14.3)]. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times ULN, total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients having an absolute neutrophil count < 500/µL, platelet count < 30,000/µL, prothrombin time or activated partial thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement for strong CYP3A inhibitors or inducers. Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonist.</paragraph>
<paragraph>In ASCEND, 154 patients received CALQUENCE (100 mg approximately every 12 hours until disease progression or unacceptable toxicity), 118 received idelalisib (150 mg approximately every 12 hours until disease progression or unacceptable toxicity) with up to 8 infusions of a rituximab product, and 35 received up to 6 cycles of bendamustine and a rituximab product. The median age overall was 68 years (range: 32-90); 67% were male; 92% were white; and 88% had an ECOG performance status of 0 or 1.</paragraph>
<paragraph>In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.</paragraph>
<paragraph>In recipients of CALQUENCE, permanent discontinuation due to an adverse reaction occurred in 10% of patients, most frequently due to second primary malignancies followed by infection. Adverse reactions led to dosage interruptions of CALQUENCE in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and dose reduction in 3.9% of patients.</paragraph>
<paragraph>Selected adverse reactions are described in Table 10 and non-hematologic laboratory abnormalities are described in Table 11. These tables reflect exposure to CALQUENCE with median duration of 15.7 months with 94% of patients on treatment for greater than 6 months and 86% of patients on treatment for greater than 12 months. The median duration of exposure to idelalisib was 11.5 months with 72% of patients on treatment for greater than 6 months and 48% of patients on treatment for greater than 12 months. Eighty-three percent of patients completed 6 cycles of bendamustine and rituximab product. </paragraph>
<table cellpadding="0pt" width="100%">
<caption>Table 10: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND)</caption>
<col width="26%"/>
<col width="22%"/>
<col width="11%"/>
<col width="11%"/>
<col width="10%"/>
<col width="10%"/>
<col width="10%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Body System</content>
</paragraph>
<paragraph>
<content styleCode="bold">Adverse Reaction</content>
<footnote ID="_Ref25061262">Per NCI CTCAE version 4.03</footnote>
</paragraph>
<paragraph>
<content styleCode="bold"> </content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">CALQUENCE</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=154</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Idelalisib plus Rituximab</content>
</paragraph>
<paragraph>
<content styleCode="bold">Product N=118</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph>
<content styleCode="bold">Bendamustine plus Rituximab Product</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=35</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Grade ≥ 3 (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="bottom">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Infections</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Infection<footnote ID="_Ref25061359">Includes any adverse reactions involving infection or febrile neutropenia</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>56</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15<footnote ID="_Ref25237547">Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>65</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>28<footnoteRef IDREF="_Ref25237547"/>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>49</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>11</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Upper respiratory tract infection<footnote ID="_Ref25245332">Upper respiratory tract infection, rhinitis and nasopharyngitis</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>29</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.9</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>26</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>3.4</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>17</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.9</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Lower respiratory tract infection<footnote ID="_Ref25061420">Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>23</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>26</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>14</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="bottom">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Blood and lymphatic system disorders</content>
<footnote ID="_Ref25245351">Derived from adverse reaction and laboratory data</footnote>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Neutropenia<footnote ID="_Ref25061506">Includes neutropenia, neutrophil count decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>48</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>23</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>79</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>53</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>80</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>40</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Anemia<footnote ID="_Ref25061530">Includes anemia, red blood cell decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>47</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>45</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>8</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>57</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>17</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Thrombocytopenia<footnote ID="_Ref25061552">Includes thrombocytopenia, platelet count decreased, and related laboratory data</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>33</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>41</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>13</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>54</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Lymphocytosis<footnote ID="_Ref25061580">Includes lymphocytosis, lymphocyte count increased and related laboratory data</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>26</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>19</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>23</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>18</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.9</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.9</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Nervous system disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Headache</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>22</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0.6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Gastrointestinal disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Diarrhea<footnote ID="_Ref25245398">Includes colitis, diarrhea, and enterocolitis</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>18</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.3</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>49</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>25</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>14</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Vascular disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Hemorrhage<footnote ID="_Ref25061630">Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>16</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.3</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>5</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.7</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.9</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">General disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Fatigue<footnote ID="_Ref25245416">Includes asthenia, fatigue, and lethargy</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.9</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>13</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0.8</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>31</item>
</list>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>6</item>
</list>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Rrule Lrule Botrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>
<content styleCode="bold">Musculoskeletal and connective tissue disorders</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>Musculoskeletal Pain<footnote ID="_Ref25245423">Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain</footnote>
</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.3</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>15</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>1.7</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>2.9</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<list listType="unordered">
<item>
<caption> </caption>0</item>
</list>
</td>
</tr>
</tbody>
</table>
<paragraph>Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included:</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>
<content styleCode="italics">Skin and subcutaneous disorders:</content> bruising (10%), rash (9%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Neoplasms:</content> second primary malignancy (12%), non-melanoma skin cancer (6%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Musculoskeletal and connective tissue disorders:</content> arthralgia (8%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Cardiac disorders:</content> atrial fibrillation or flutter (5%), hypertension (3.2%)</item>
<item>
<caption>•</caption>
<content styleCode="italics">Infection:</content> herpesvirus infection (4.5%)</item>
</list>
<table ID="_RefID0ECBAI" cellpadding="0pt" width="100%">
<caption>Table 11: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)</caption>
<col width="23%"/>
<col width="23%"/>
<col width="11%"/>
<col width="11%"/>
<col width="11%"/>
<col width="11%"/>
<col width="11%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Laboratory Abnormality</content>
<footnote ID="_Ref25062183">Excludes electrolytes</footnote>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">CALQUENCE </content>
<br/>
<content styleCode="bold">N=154</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Idelalisib plus Rituximab Product</content>
<br/>
<content styleCode="bold">N=118</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Bendamustine plus Rituximab Product</content>
<br/>
<content styleCode="bold">N=35</content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">All</content>
<br/>
<content styleCode="bold">Grades (%)</content>
</th>
<th align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Grade ≥ 3 (%)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>Uric acid increase</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>23</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>ALT increase</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>59</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>2.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>AST increase</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>48</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>2.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>Bilirubin increase</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>1.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>26</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>11</paragraph>
</td>
</tr>
<tr>
<td colspan="7" styleCode="Botrule " valign="middle">
<paragraph>Per NCI CTCAE version 5</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20250116"/>
</section>
</component>
<component>
<section ID="ID_0844fada-8168-4497-91c3-cf8d567b52a9">
<id root="74912c95-2d7e-4b5c-b3c4-ef539b74e6d6"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>6.2 Postmarketing Experience </title>
<text>
<paragraph>The following adverse reactions have been identified during postapproval use of CALQUENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</paragraph>
<list listType="unordered">
<item>
<caption>•</caption>Cardiac disorders: ventricular arrhythmias</item>
<item>
<caption>•</caption>Hepatobiliary disorders: drug induced liver injury</item>
</list>
</text>
<effectiveTime value="20230605"/>
</section>
</component>
</section>