<?xml version="1.0" encoding="UTF-8"?><title>These highlights do not include all the information needed to use CALQUENCE safely and effectively. See full prescribing information for CALQUENCE.<br/>CALQUENCE^® (acalabrutinib) capsules, for oral use<br/>Initial U.S. Approval: 2017</title>

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classCode="IACT"> <ingredientSubstance> <code code="15FIX9V2JP" codeSystem="2.16.840.1.113883.4.9"/> <name>TITANIUM DIOXIDE</name> </ingredientSubstance> </ingredient> <ingredient classCode="IACT"> <ingredientSubstance> <code code="EX438O2MRT" codeSystem="2.16.840.1.113883.4.9"/> <name>FERRIC OXIDE YELLOW</name> </ingredientSubstance> </ingredient> <ingredient classCode="IACT"> <ingredientSubstance> <code code="L06K8R7DQK" codeSystem="2.16.840.1.113883.4.9"/> <name>FD&amp;C BLUE NO. 2</name> </ingredientSubstance> </ingredient> <ingredient classCode="IACT"> <ingredientSubstance> <code code="ETJ7Z6XBU4" codeSystem="2.16.840.1.113883.4.9"/> <name>SILICON DIOXIDE</name> </ingredientSubstance> </ingredient> <asContent> <quantity> <numerator unit="1" value="60"/> <denominator value="1"/> </quantity> <containerPackagedProduct> <code code="0310-0512-60" codeSystem="2.16.840.1.113883.6.69"/> <formCode code="C43169" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="BOTTLE"/> 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displayName="Type 0: Not a Combination Product"/> </characteristic> </subjectOf> </asContent> </manufacturedProduct> <subjectOf> <approval> <id extension="NDA210259" root="2.16.840.1.113883.3.150"/> <code code="C73594" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="NDA"/> <author> <territorialAuthority> <territory> <code code="USA" codeSystem="2.16.840.1.113883.5.28"/> </territory> </territorialAuthority> </author> </approval> </subjectOf> <subjectOf> <marketingAct> <code code="C53292" codeSystem="2.16.840.1.113883.3.26.1.1"/> <statusCode code="active"/> <effectiveTime> <low value="20171031"/> </effectiveTime> </marketingAct> </subjectOf> <subjectOf> <characteristic classCode="OBS"> <code code="SPLCOLOR" codeSystem="2.16.840.1.113883.1.11.19255"/> <value code="C48330" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="YELLOW"> <originalText>blue cap</originalText> </value> </characteristic> </subjectOf> <subjectOf> <characteristic classCode="OBS"> <code code="SPLSIZE" codeSystem="2.16.840.1.113883.1.11.19255"/> <value unit="mm" value="1"/> </characteristic> </subjectOf> <subjectOf> <characteristic classCode="OBS"> <code code="SPLSHAPE" codeSystem="2.16.840.1.113883.1.11.19255"/> <value code="C48336" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="CAPSULE"/> </characteristic> </subjectOf> <subjectOf> <characteristic classCode="OBS"> <code code="SPLSCORE" codeSystem="2.16.840.1.113883.1.11.19255"/> <value value="1"/> </characteristic> </subjectOf> <subjectOf> <characteristic classCode="OBS"> <code code="SPLIMPRINT" codeSystem="2.16.840.1.113883.1.11.19255"/> <value>ACA;100</value> </characteristic> </subjectOf> <consumedIn> <substanceAdministration> <routeCode code="C38288" codeSystem="2.16.840.1.113883.3.26.1.1" displayName="ORAL"/> </substanceAdministration> </consumedIn> </manufacturedProduct> </subject> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_3faf9c49-dbe8-45b1-866e-93c44943b7de"> <id root="db962df9-00db-4d2f-a577-6faabaccdc66"/> <code code="43683-2" codeSystem="2.16.840.1.113883.6.1" displayName="RECENT MAJOR CHANGES SECTION"/> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <paragraph>Indications and Usage <linkHtml href="#ID_c0581d48-094b-47c1-9adc-a82f10d21dad">(1.2)</linkHtml>                                                        11/2019</paragraph> <paragraph>Dosage and Administration <linkHtml href="#ID_3a3bdb4e-74b6-4456-a7fd-401dc35bac4f">(2.2)</linkHtml>                                               11/2019</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_4947cb2d-0857-4bae-9c53-e09795704151"> <id root="d20720a1-1a61-4d24-8ac0-fae627e25eda"/> <code code="34067-9" codeSystem="2.16.840.1.113883.6.1" displayName="INDICATIONS &amp; USAGE SECTION"/> <title>1 INDICATIONS AND USAGE </title> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <paragraph>CALQUENCE is a kinase inhibitor indicated for the treatment of adult patients with:</paragraph> <list listType="unordered"> <item> <caption>•</caption>Mantle cell lymphoma (MCL) who have received at least one prior therapy. <linkHtml href="#ID_23014fac-6d01-4501-a9f6-4421e9fe2de4">(1.1)</linkHtml> <br/>This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. <linkHtml href="#ID_23014fac-6d01-4501-a9f6-4421e9fe2de4">(1.1,</linkHtml> <linkHtml href="#ID_c234c84a-4750-49ce-938e-eef3fe31e927">14.1)</linkHtml> </item> <item> <caption>•</caption>Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). <linkHtml href="#ID_c0581d48-094b-47c1-9adc-a82f10d21dad">(1.2)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_23014fac-6d01-4501-a9f6-4421e9fe2de4"> <id root="91404907-7d39-4aa3-8e53-91566cb34eae"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.1 Mantle Cell Lymphoma </title> <text> <paragraph>CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.</paragraph> <paragraph>This indication is approved under accelerated approval based on overall response rate <content styleCode="italics">[see <linkHtml href="#ID_c234c84a-4750-49ce-938e-eef3fe31e927">Clinical Studies (14.1)</linkHtml>]</content>. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_c0581d48-094b-47c1-9adc-a82f10d21dad"> <id root="081ba5b6-ebeb-467a-8d8b-791dfb31542c"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title> <content styleCode="xmChange">1.2 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma</content> </title> <text> <paragraph> <content styleCode="xmChange">CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)</content>.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_7631b9e1-45d6-48c5-be90-d4f85e18708d"> <id root="c9cd8c80-da51-4a6d-82dd-6579c3ec502b"/> <code code="34068-7" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE &amp; ADMINISTRATION SECTION"/> <title>2 DOSAGE AND ADMINISTRATION </title> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Recommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food. <linkHtml href="#ID_1d2f0370-6594-4e65-addb-1bb7725a3e86">(2.1)</linkHtml> </item> <item> <caption>•</caption>Advise patients not to break, open, or chew capsules. <linkHtml href="#ID_1d2f0370-6594-4e65-addb-1bb7725a3e86">(2.1)</linkHtml> </item> <item> <caption>•</caption>Manage toxicities using treatment interruption, dose reduction, or discontinuation. <linkHtml href="#ID_3a3bdb4e-74b6-4456-a7fd-401dc35bac4f">(2.2)</linkHtml> </item> <item> <caption>•</caption>Avoid CALQUENCE in patients with severe hepatic impairment <linkHtml href="#ID_3a3bdb4e-74b6-4456-a7fd-401dc35bac4f">(2.2,</linkHtml> <linkHtml href="#ID_521f2bfe-a95d-4a0b-8696-47f95342c0ef">8.6)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_1d2f0370-6594-4e65-addb-1bb7725a3e86"> <id root="657ca832-6676-497b-9f52-494f176f464d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.1 Recommended Dosage </title> <text> <paragraph> <content styleCode="underline">CALQUENCE as Monotherapy</content> </paragraph> <paragraph>For patients with MCL, CLL, or SLL, the recommended dose of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.</paragraph> <paragraph> <content styleCode="underline">CALQUENCE in Combination with Obinutuzumab</content> </paragraph> <paragraph>For patients with previously untreated CLL or SLL, the recommended dose of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle 1 (each cycle is 28 days). Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day.</paragraph> <paragraph>Advise patients to swallow capsule whole with water. Advise patients not to open, break or chew the capsules. CALQUENCE may be taken with or without food. If a dose of CALQUENCE is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra capsules of CALQUENCE should not be taken to make up for a missed dose.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_3a3bdb4e-74b6-4456-a7fd-401dc35bac4f"> <id root="bbf5badd-0641-4792-ace1-655d6da53122"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title> <content styleCode="xmChange">2.2 Recommended Dosage for Hepatic Impairment</content> </title> <text> <paragraph> <content styleCode="xmChange">Avoid administration of CALQUENCE in patients with severe hepatic impairment.</content> </paragraph> <paragraph> <content styleCode="xmChange">Dose modifications are not required for patients with mild or moderate hepatic impairment <content styleCode="italics">[see </content> </content> <content styleCode="italics"> <linkHtml href="#ID_521f2bfe-a95d-4a0b-8696-47f95342c0ef">Use in Specific Populations (8.6)</linkHtml> <content styleCode="xmChange"> and </content> <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</linkHtml> <content styleCode="xmChange">]</content> </content> <content styleCode="xmChange">.</content> </paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_9ba703c9-7b46-4239-9ed4-061924b069b9"> <id root="40614eb9-4bf3-4629-8549-0e160ea10551"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.3 Recommended Dosage for Drug Interactions </title> <text> <paragraph> <content styleCode="underline">Dose Modifications for Use with CYP3A Inhibitors or Inducers</content> </paragraph> <paragraph>These are described in Table 1 <content styleCode="italics">[see <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">Drug Interactions (7)</linkHtml>]</content>.</paragraph> <table ID="_RefID0E6OAC" width="100%"> <caption>Table 1: Recommended Dose Modifications for Use with CYP3A Inhibitors or Inducers</caption> <col width="11%"/> <col width="21%"/> <col width="68%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">CYP3A </content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Co-administered Drug</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Recommended CALQUENCE use</content> </paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Inhibition</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Strong CYP3A inhibitor</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Avoid concomitant use.</paragraph> <paragraph>If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Moderate CYP3A inhibitor</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>100 mg once daily.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>Induction</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>Strong CYP3A inducer</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>Avoid concomitant use.</paragraph> <paragraph>If these inducers cannot be avoided, increase CALQUENCE dose to 200 mg approximately every 12 hours.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Concomitant Use with Gastric Acid Reducing Agents</content> </paragraph> <paragraph> <content styleCode="italics">Proton Pump Inhibitors:</content> Avoid concomitant use <content styleCode="italics">[see <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">Drug Interactions (7)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="italics">H2-Receptor Antagonists:</content> Take CALQUENCE 2 hours before taking a H2-receptor antagonist <content styleCode="italics">[see <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">Drug Interactions (7)</linkHtml>]</content>.</paragraph> <paragraph>Antacids: Separate dosing by at least 2 hours <content styleCode="italics">[see <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">Drug Interactions (7)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_a7dd6d30-6cb7-4b03-b1f7-7908504c1851"> <id root="1b774307-69a5-492b-8480-9e86ce21d026"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.4 Dose Modifications for Adverse Reactions </title> <text> <paragraph>Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 2.</paragraph> <table ID="_RefID0EXCAE" width="100%"> <caption>Table 2: Recommended Dose Modifications for Adverse Reactions</caption> <col width="26%"/> <col width="19%"/> <col width="55%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Event</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction Occurrence</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Dose Modification</content> </paragraph> <paragraph>(Starting dose = 100 mg approximately every 12 hours)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Grade 3 or greater non-hematologic toxicities,</paragraph> <paragraph>Grade 3 thrombocytopenia with bleeding,</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>First and Second</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Interrupt CALQUENCE.</paragraph> <paragraph>Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="top"> <paragraph>Grade 4 thrombocytopenia or</paragraph> <paragraph>Grade 4 neutropenia lasting longer than 7 days</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Third</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Interrupt CALQUENCE.</paragraph> <paragraph>Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Fourth</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Discontinue CALQUENCE.</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Botrule " valign="top"> <paragraph>Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).</paragraph> </td> </tr> </tbody> </table> <paragraph>Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_66ed13fe-9ab0-4d0e-8454-16f3c25bcf94"> <id root="0dbe3c60-cfae-4c74-a614-3037fdf62a3b"/> <code code="43678-2" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE FORMS &amp; STRENGTHS SECTION"/> <title>3 DOSAGE FORMS AND STRENGTHS </title> <text> <paragraph>100 mg capsules.</paragraph> </text> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <paragraph>Capsules: 100 mg. <linkHtml href="#ID_66ed13fe-9ab0-4d0e-8454-16f3c25bcf94">(3)</linkHtml> </paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_0dfc193c-7e8b-4fd1-9306-375842449890"> <id root="df90e3e1-899c-4a9a-a511-97ab5acffe3e"/> <code code="34070-3" codeSystem="2.16.840.1.113883.6.1" displayName="CONTRAINDICATIONS SECTION"/> <title>4 CONTRAINDICATIONS </title> <text> <paragraph>None.</paragraph> </text> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <paragraph>None. <linkHtml href="#ID_0dfc193c-7e8b-4fd1-9306-375842449890">(4)</linkHtml> </paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_5c2015ae-ca1d-4f69-8fa1-21502ea47bf3"> <id root="7846ec6e-870d-4a6b-a4ec-562c031e5221"/> <code code="43685-7" codeSystem="2.16.840.1.113883.6.1" displayName="WARNINGS AND PRECAUTIONS SECTION"/> <title>5 WARNINGS AND PRECAUTIONS </title> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">Serious and Opportunistic Infections</content>: Monitor for signs and symptoms of infection and treat promptly. <linkHtml href="#ID_a4c950e2-42fd-447e-9d4a-ea48d372a53f">(5.1)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">Hemorrhage</content>: Monitor for bleeding and manage appropriately. <linkHtml href="#ID_76c626fd-a938-4c7d-a620-957d6afcaca7">(5.2)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">Cytopenias</content>: Monitor complete blood counts regularly. <linkHtml href="#ID_77b0700d-b56a-499d-8550-6b11b73f6425">(5.3)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">Second Primary Malignancies</content>: Other malignancies have occurred, including skin cancers and other solid tumors. Advise patients to use sun protection. <linkHtml href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">(5.4)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">Atrial Fibrillation and Flutter</content>: Monitor for symptoms of arrhythmias and manage. <linkHtml href="#ID_b13613ac-a265-4264-9e98-65d552d22e92">(5.5)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_a4c950e2-42fd-447e-9d4a-ea48d372a53f"> <id root="8b257c0d-cec4-41d7-90ad-6f9b22ce5e26"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.1 Serious and Opportunistic Infections </title> <text> <paragraph>Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE. </paragraph> <paragraph>Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, <content styleCode="italics">Pneumocystis jiroveci</content> pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_76c626fd-a938-4c7d-a620-957d6afcaca7"> <id root="e0ed152a-87d4-400a-9d11-709e406e9c61"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.2 Hemorrhage </title> <text> <paragraph>Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.</paragraph> <paragraph>Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.</paragraph> <paragraph>Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_77b0700d-b56a-499d-8550-6b11b73f6425"> <id root="7ca8dc9d-cbfa-4405-bd2d-a5da1d143e4d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.3 Cytopenias </title> <text> <paragraph>Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted <content styleCode="italics">[see<linkHtml href="#ID_a7dd6d30-6cb7-4b03-b1f7-7908504c1851"> Dose Modifications for Adverse Reactions (2.4)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b"> <id root="3a932d6f-1ac4-4915-b238-4681669fc663"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.4 Second Primary Malignancies </title> <text> <paragraph>Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_b13613ac-a265-4264-9e98-65d552d22e92"> <id root="157c7437-5630-41ce-bdcd-e618549bd2ba"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.5 Atrial Fibrillation and Flutter </title> <text> <paragraph>Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_411ecced-cfea-451d-b533-987a2068e927"> <id root="dee9361c-53d5-4592-a7bd-1b062a5e7d8b"/> <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 <linkHtml href="#ID_a4c950e2-42fd-447e-9d4a-ea48d372a53f">Warnings and Precautions (5.1)</linkHtml>]</content> </item> <item> <caption>•</caption>Hemorrhage <content styleCode="italics">[see <linkHtml href="#ID_76c626fd-a938-4c7d-a620-957d6afcaca7">Warnings and Precautions (5.2)</linkHtml>]</content> </item> <item> <caption>•</caption>Cytopenias <content styleCode="italics">[see <linkHtml href="#ID_cf4be055-4786-457c-8934-4b05fafa7114">Warnings and Precautions (5.3)</linkHtml>]</content> </item> <item> <caption>•</caption>Second Primary Malignancies <content styleCode="italics">[see <linkHtml href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">Warnings and Precautions (5.4)</linkHtml>]</content> </item> <item> <caption>•</caption>Atrial Fibrillation and Flutter <content styleCode="italics">[see <linkHtml href="#ID_b13613ac-a265-4264-9e98-65d552d22e92">Warnings and Precautions (5.5)</linkHtml>]</content> </item> </list> </text> <effectiveTime value="20191122"/> <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> <component> <section ID="ID_81dc654f-96ff-4182-a11c-59a3a4d5515e"> <id root="4f4b0a67-2083-4780-bb9d-a8aac5e5bb61"/> <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>As 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 1029 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 820 patients in 6 trials, and CALQUENCE with obinutuzumab in 209 patients in 2 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 79% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.</paragraph> <paragraph> <content styleCode="underline">Mantle Cell Lymphoma</content> </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_c234c84a-4750-49ce-938e-eef3fe31e927">Clinical Studies (14.1)</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 3 and 4 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.</paragraph> <table ID="_RefID0E4OAE" width="100%"> <caption>Table 3: 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 4: 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="underline">Chronic Lymphocytic Leukemia</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 <linkHtml href="#ID_c90b2bd1-ad84-4a20-90a2-bab467820996">Clinical Studies (14.2)</linkHtml>]</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 <linkHtml href="#ID_c90b2bd1-ad84-4a20-90a2-bab467820996">Clinical Studies (14.2)</linkHtml>]</content>.</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 &lt; 65 years of age with a total Cumulative Illness Rating Scale (CIRS) &gt; 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases ≤ 3 times upper limit of normal (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 5 and 6 presents adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.</paragraph> <table ID="_RefID0ED3AE" cellpadding="0pt" width="100%"> <caption>Table 5: 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 &lt; 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 6: 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 1.5 to 3 times the upper limit of normal 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) <content styleCode="italics">[see <linkHtml href="#ID_c90b2bd1-ad84-4a20-90a2-bab467820996">Clinical Studies (14.2)</linkHtml>]</content>. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients having an absolute neutrophil count &lt; 500/µL, platelet count &lt; 30,000/µL, prothrombin time or activated partial thromboplastin time &gt; 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 &gt; 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 7 and non-hematologic laboratory abnormalities are described in Table 8. 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 ID="_RefID0EXDBG" cellpadding="0pt" width="100%"> <caption>Table 7: 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 &lt; 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 8: 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="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74"> <id root="a62dbb75-e4ec-48e4-ad3d-87696eca596a"/> <code code="34073-7" codeSystem="2.16.840.1.113883.6.1" displayName="DRUG INTERACTIONS SECTION"/> <title>7 DRUG INTERACTIONS </title> <text> <table width="100%"> <col width="19%"/> <col width="30%"/> <col width="51%"/> <tbody> <tr> <td colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Strong CYP3A Inhibitors</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Co-administration of CALQUENCE with a strong CYP3A inhibitor (itraconazole) increased acalabrutinib plasma concentrations <content styleCode="italics">[see <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</linkHtml>]</content>.</item> <item> <caption>•</caption>Increased acalabrutinib concentrations may result in increased toxicity.</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Prevention or Management</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Avoid co-administration of strong CYP3A inhibitors with CALQUENCE.</item> <item> <caption>•</caption>Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE <content styleCode="italics">[<linkHtml href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">see Recommended Dosage for Drug Interactions (2.3)</linkHtml>]</content>.</item> </list> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Moderate CYP3A Inhibitors</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations <content styleCode="italics">[see <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</linkHtml>].</content> </item> <item> <caption>•</caption>Increased acalabrutinib concentrations may result in increased toxicity.</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Prevention or Management</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.</item> </list> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Strong CYP3A Inducers</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Co-administration of CALQUENCE with a strong CYP3A inducer (rifampin) decreased acalabrutinib plasma concentrations <content styleCode="italics">[see <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</linkHtml>]</content>.</item> <item> <caption>•</caption>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Prevention or Management</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Avoid co-administration of strong CYP3A inducers with CALQUENCE.</item> <item> <caption>•</caption>If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.</item> </list> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Gastric Acid Reducing Agents</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <list listType="unordered"> <item> <caption>•</caption>Co-administration of CALQUENCE with a proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations <content styleCode="italics">[<linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">see Clinical Pharmacology (12.3)</linkHtml>]</content>.</item> <item> <caption>•</caption>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</item> <item> <caption>•</caption>If treatment with a gastric acid reducing agent is required, consider using a H2‑receptor antagonist (e.g., ranitidine or famotidine) or an antacid (e.g., calcium carbonate).</item> </list> </td> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="italics">Prevention or Management</content> </paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Antacids</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Separate dosing by at least 2 hours <content styleCode="italics">[see <linkHtml href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">Recommended Dosage for Drug Interactions (2.3)</linkHtml>]</content>.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>H2-receptor antagonists</paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Take CALQUENCE 2 hours before taking the H2-receptor antagonist <content styleCode="italics">[see <linkHtml href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">Recommended Dosage for Drug Interactions (2.3)</linkHtml>].</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>Proton pump inhibitors</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>Avoid co-administration. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="underline">CYP3A Inhibitors:</content> Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended. <linkHtml href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">(2.3,</linkHtml> <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">7,</linkHtml> <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">12.3)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">CYP3A Inducers:</content> Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended. <linkHtml href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">(2.3,</linkHtml> <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">7,</linkHtml> <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">12.3)</linkHtml> </item> <item> <caption>•</caption> <content styleCode="underline">Gastric Acid Reducing Agents:</content> Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids. <linkHtml href="#ID_a7dd6d30-6cb7-4b03-b1f7-7908504c1851">(2.4,</linkHtml> <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">7,</linkHtml> <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">12.3)</linkHtml> </item> </list> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_e35714fd-dc84-4eac-b1b8-80ef00b029d0"> <id root="eb148983-7003-43ef-9d92-1caae3702a11"/> <code code="43684-0" codeSystem="2.16.840.1.113883.6.1" displayName="USE IN SPECIFIC POPULATIONS SECTION"/> <title>8 USE IN SPECIFIC POPULATIONS </title> <effectiveTime value="20191122"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Pregnancy: May cause fetal harm and dystocia. <linkHtml href="#ID_dbea9b54-92f3-4c32-bc14-137edcb40897">(8.1)</linkHtml> </item> <item> <caption>•</caption>Lactation: Advise not to breastfeed <linkHtml href="#ID_0d455326-8dc0-4c3d-8d1e-0a74f652160a">(8.2)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_dbea9b54-92f3-4c32-bc14-137edcb40897"> <id root="ae71cc9d-ce91-49b6-a007-6d657adf95da"/> <code code="42228-7" codeSystem="2.16.840.1.113883.6.1" displayName="PREGNANCY SECTION"/> <title>8.1 Pregnancy </title> <text> <paragraph> <content styleCode="underline">Risk Summary</content> </paragraph> <paragraph>Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours (<content styleCode="italics">see Data</content>). Advise pregnant women of the potential risk to a fetus.</paragraph> <paragraph>The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.</paragraph> <paragraph> <content styleCode="underline">Data</content> </paragraph> <paragraph> <content styleCode="italics">Animal Data</content> </paragraph> <paragraph>In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9-times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.</paragraph> <paragraph>In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours.</paragraph> <paragraph>In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5-times the AUC in patients at 100 mg approximately every 12 hours.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_0d455326-8dc0-4c3d-8d1e-0a74f652160a"> <id root="7df50e60-9916-465e-9a57-da718ad1a714"/> <code code="77290-5" codeSystem="2.16.840.1.113883.6.1" displayName="LACTATION SECTION"/> <title>8.2 Lactation </title> <effectiveTime value="20191122"/> <component> <section ID="ID_5e6b7b7c-b2cc-4124-8b94-44f8219aa644"> <id root="5e0f6b32-d525-41bb-97aa-33f452b19e4b"/> <code code="69759-9" codeSystem="2.16.840.1.113883.6.1" displayName="RISKS"/> <title> <content styleCode="underline">Risk Summary</content> </title> <text> <paragraph>No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from CALQUENCE, advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section> </component> <component> <section ID="ID_cf4be055-4786-457c-8934-4b05fafa7114"> <id root="7a016569-3e85-4eb8-8432-b811f042f19f"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.3 Females and Males of Reproductive Potential </title> <text> <paragraph> <content styleCode="underline">Pregnancy</content> </paragraph> <paragraph>Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.</paragraph> <paragraph> <content styleCode="underline">Contraception </content> </paragraph> <paragraph> <content styleCode="italics">Females</content> </paragraph> <paragraph>CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women <content styleCode="italics">[see <linkHtml href="#ID_dbea9b54-92f3-4c32-bc14-137edcb40897">Use in Specific Populations (8.1)</linkHtml>]</content>. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_d2eb1949-49d7-4009-b056-4544a88d0e11"> <id root="798f2672-da26-4071-8fdd-231dfda36e2e"/> <code code="34081-0" codeSystem="2.16.840.1.113883.6.1" displayName="PEDIATRIC USE SECTION"/> <title>8.4 Pediatric Use </title> <text> <paragraph>The safety and efficacy of CALQUENCE in pediatric patients have not been established.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_9d53b612-a4aa-4464-bb17-baeb4be01b3c"> <id root="e5a143e0-26d2-45a8-b3c7-f02178e9b393"/> <code code="34082-8" codeSystem="2.16.840.1.113883.6.1" displayName="GERIATRIC USE SECTION"/> <title>8.5 Geriatric Use </title> <text> <paragraph>Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients ≥ 65 years and younger.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_521f2bfe-a95d-4a0b-8696-47f95342c0ef"> <id root="1779402e-82a3-4e01-b834-76d59edd8ae0"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.6 Hepatic Impairment </title> <text> <paragraph>Avoid administration of CALQUENCE in patients with severe hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment <content styleCode="italics">[see <linkHtml href="#ID_3a3bdb4e-74b6-4456-a7fd-401dc35bac4f">Recommended Dosage for Hepatic Impairment (2.2)</linkHtml> and <linkHtml href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_c2612f4e-ba48-4bc0-99aa-ffad39ba39e5"> <id root="a7ec60b7-63f6-410f-80b6-2793917818df"/> <code code="34089-3" codeSystem="2.16.840.1.113883.6.1" displayName="DESCRIPTION SECTION"/> <title>11 DESCRIPTION </title> <text> <paragraph>CALQUENCE (acalabrutinib) is an inhibitor of Bruton tyrosine kinase (BTK). The molecular formula for acalabrutinib is C₂₆H₂₃N₇O₂, and the molecular weight is 465.51. The chemical name is 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide.</paragraph> <paragraph>The chemical structure of acalabrutinib is shown below:</paragraph> <renderMultiMedia ID="id1987127014" referencedObject="ID_0f7e32f5-a40c-42d4-be56-1b2fd55d71e8"/> <paragraph>Acalabrutinib is a white to yellow powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6.</paragraph> <paragraph>CALQUENCE capsules for oral administration contains 100 mg acalabrutinib and the following inactive ingredients: silicified microcrystalline cellulose, partially pregelatinized starch, magnesium stearate, and sodium starch glycolate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, FD&amp;C Blue 2 and is imprinted with edible black ink.</paragraph> </text> <effectiveTime value="20191122"/> <component> <observationMedia ID="ID_0f7e32f5-a40c-42d4-be56-1b2fd55d71e8"> <text>Chemical_Structure</text> <value mediaType="image/jpeg"> <reference value="chemical_structure.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_d48d0f8e-3130-443d-a4ff-f49cbf1c4a10"> <id root="482216b8-f5cc-442e-baad-c1e0a5b69a41"/> <code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/> <title>12 CLINICAL PHARMACOLOGY </title> <effectiveTime value="20191122"/> <component> <section ID="ID_f3bda14e-cdcf-4334-8c04-b91b2c302f90"> <id root="ee502d55-986b-47bb-a21b-79d401072f61"/> <code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/> <title>12.1 Mechanism of Action </title> <text> <paragraph>Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_ecb541a7-b187-4b56-8daa-4f1995c9cf56"> <id root="d4fda78b-e705-446c-b59f-baf81af17d00"/> <code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/> <title>12.2 Pharmacodynamics </title> <text> <paragraph>In patients with B-cell malignancies dosed with 100 mg approximately every 12 hours, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.</paragraph> <paragraph> <content styleCode="underline">Cardiac Electrophysiology</content> </paragraph> <paragraph>The effect of acalabrutinib on the QTc interval was evaluated in a randomized, double-blind, double-dummy, placebo‑ and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of a single dose of acalabrutinib that is the 4-fold maximum recommended single dose did not prolong the QTc interval to any clinically relevant extent (i.e., ≥ 10 ms).</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_7e085cea-9439-4c36-9305-3c4a71a4e52f"> <id root="aa911145-8a99-45d1-86e7-dcf6f6a73f8d"/> <code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/> <title>12.3 Pharmacokinetics </title> <text> <paragraph>Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and its active metabolite, ACP-5862, exposures increase with dose across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose) in patients with B-cell malignancies. At the recommended dose of 100 mg twice daily, the geometric mean (% coefficient of variation [CV]) daily area under the plasma drug concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1843 (38%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively.</paragraph> <paragraph> <content styleCode="underline">Absorption</content> </paragraph> <paragraph>The geometric mean absolute bioavailability of acalabrutinib was 25%. Median [min, max] time to peak acalabrutinib plasma concentrations (Tmax) was 0.9 [0.5, 1.9] hours, and 1.6 [0.9, 2.7] hour for ACP-5862.</paragraph> <paragraph> <content styleCode="italics">Effect of Food</content> </paragraph> <paragraph>In healthy subjects, administration of a single 75 mg dose of acalabrutinib (0.75 times the approved recommended single dose) with a high-fat, high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting C_max decreased by 73% and T_max was delayed 1-2 hours.</paragraph> <paragraph> <content styleCode="underline">Distribution</content> </paragraph> <paragraph>Reversible binding to human plasma protein was 97.5% for acalabrutinib and 98.6% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The geometric mean (% CV) steady-state volume of distribution (Vss) was approximately 101 (52%) L for acalabrutinib and 67 (32%) L for ACP-5862.</paragraph> <paragraph> <content styleCode="underline">Elimination</content> </paragraph> <paragraph>The geometric mean (% CV) terminal elimination half-life (t1/2) was 1 (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862. The geometric mean (%CV) apparent oral clearance (CL/F) was 71 (35%) L/hr for acalabrutinib and 13 (42%) L/hr for ACP-5862.</paragraph> <paragraph> <content styleCode="italics">Metabolism</content> </paragraph> <paragraph>Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on <content styleCode="italics">in vitro</content> studies. ACP-5862 was identified as the major active metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.</paragraph> <paragraph> <content styleCode="italics">Excretion</content> </paragraph> <paragraph>Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and feces.</paragraph> <paragraph> <content styleCode="underline">Specific Populations</content> </paragraph> <paragraph> <content styleCode="italics">Age, Race, and Body Weight</content> </paragraph> <paragraph>Age (32 to 90 years), sex, race (Caucasian, African American), and body weight (40 to 149 kg) did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.</paragraph> <paragraph> <content styleCode="italics">Renal Impairment</content> </paragraph> <paragraph>No clinically relevant PK difference was observed in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR &lt; 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.</paragraph> <paragraph> <content styleCode="italics">Hepatic Impairment</content> </paragraph> <paragraph>The AUC of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was observed in subjects with severe hepatic impairment (Child-Pugh Class C) compared to subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and ACP-5862 were observed in patients with mild or moderate hepatic impairment (total bilirubin less and equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin greater than ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST within ULN).</paragraph> <paragraph> <content styleCode="underline">Drug Interaction Studies</content> </paragraph> <paragraph> <content styleCode="italics">Effect of CYP3A Inhibitors on Acalabrutinib</content> </paragraph> <paragraph>Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased the acalabrutinib C_max by 3.9-fold and AUC by 5.1-fold in healthy subjects.</paragraph> <paragraph>Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib C_max and AUC approximately 2- to 3-fold.</paragraph> <paragraph> <content styleCode="italics">Effect of CYP3A Inducers on Acalabrutinib</content> </paragraph> <paragraph>Co-administration with a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib C_max by 68% and AUC by 77% in healthy subjects.</paragraph> <paragraph> <content styleCode="italics">Gastric Acid Reducing Agents</content> </paragraph> <paragraph>Acalabrutinib solubility decreases with increasing pH. Co-administration with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43%.</paragraph> <paragraph> <content styleCode="underline"> <content styleCode="italics">In Vitro </content>Studies</content> </paragraph> <paragraph> <content styleCode="italics">Metabolic Pathways</content> </paragraph> <paragraph>Acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7.</paragraph> <paragraph>Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.</paragraph> <paragraph>Based on <content styleCode="italics">in vitro</content> data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.</paragraph> <paragraph> <content styleCode="italics">Drug Transporter Systems</content> </paragraph> <paragraph>Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1, and OATP1B3. ACP-5862 is not a substrate of OATP1B1 or OATP1B3.</paragraph> <paragraph>Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K at clinically relevant concentrations.</paragraph> <paragraph>Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) by inhibition of intestinal BCRP. ACP-5862 does not inhibit BCRP at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_d4cf8d05-e1fe-4933-9a97-998ea77956f0"> <id root="11258d0a-f5c9-49a4-8167-dd6b6712b9f2"/> <code code="43680-8" codeSystem="2.16.840.1.113883.6.1" displayName="NONCLINICAL TOXICOLOGY SECTION"/> <title>13 NONCLINICAL TOXICOLOGY </title> <effectiveTime value="20191122"/> <component> <section ID="ID_a99e3efa-3978-47d4-8742-2a2a1e4dc2e5"> <id root="3d394ad6-25e1-46b3-9662-ac2fec8867f5"/> <code code="34083-6" codeSystem="2.16.840.1.113883.6.1" displayName="CARCINOGENESIS &amp; MUTAGENESIS &amp; IMPAIRMENT OF FERTILITY SECTION"/> <title>13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility </title> <text> <paragraph>Carcinogenicity studies have not been conducted with acalabrutinib.</paragraph> <paragraph>Acalabrutinib was not mutagenic in an <content styleCode="italics">in vitro</content> bacterial reverse mutation (AMES) assay or clastogenic in an <content styleCode="italics">in vitro</content> human lymphocyte chromosomal aberration assay or in an <content styleCode="italics">in vivo</content> rat bone marrow micronucleus assay.</paragraph> <paragraph>In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 11‑times, or in female rats at exposures 9‑times the AUC observed in patients at the recommended dose of 100 mg twice daily.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_0e492c3a-18dd-4d96-b301-5fd02db093aa"> <id root="9a5503ae-881f-4a56-bc0e-b55fca533c3f"/> <code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/> <title>14 CLINICAL STUDIES </title> <effectiveTime value="20191122"/> <component> <section ID="ID_c234c84a-4750-49ce-938e-eef3fe31e927"> <id root="842d8ee2-6858-495c-bfc9-0ae719cd039b"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.1 Mantle Cell Lymphoma </title> <text> <paragraph>The efficacy of CALQUENCE was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy.</paragraph> <paragraph>The median age was 68 (range 42 to 90) years, 80% were male, and 74% were Caucasian. At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1 to 5), including 18% with prior stem cell transplant. Patients who received prior treatment with BTK inhibitors were excluded. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). At baseline, 37% of patients had at least one tumor with a longest diameter ≥ 5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients.</paragraph> <paragraph>CALQUENCE was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15.2 months.</paragraph> <table ID="_RefID0ECBBI" width="100%"> <caption>Table 9: Efficacy Results in Patients with MCL in Trial LY-004</caption> <col width="43%"/> <col width="25%"/> <col width="32%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Investigator Assessed</content> </paragraph> <paragraph> <content styleCode="bold">N=124</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Independent Review Committee (IRC) Assessed</content> </paragraph> <paragraph> <content styleCode="bold">N=124</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Response Rate (ORR)</content> <footnote ID="_Ref15988074">Per 2014 Lugano Classification.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    ORR (%) [95% CI]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>81 [73, 87]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>80 [72, 87]</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Complete Response (%) [95% CI]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>40 [31, 49]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>40 [31, 49]</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Partial Response (%) [95% CI]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>41 [32, 50]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>40 [32, 50]</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Duration of Response (DoR)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Median DoR in months [range]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NE [1+ to 20+]</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NE [0+ to 20+]</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Botrule " valign="top"> <paragraph>CI= Confidence Interval; NE=Not Estimable; + indicates censored observations</paragraph> </td> </tr> </tbody> </table> <paragraph>The median time to best response was 1.9 months.</paragraph> <paragraph> <content styleCode="underline">Lymphocytosis</content> </paragraph> <paragraph>Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count (ALC) increased ≥ 50% from baseline and a post baseline assessment ≥ 5 x 10⁹) in 31.5% of patients in Trial LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.</paragraph> </text> <effectiveTime value="20191122"/> </section> </component> <component> <section ID="ID_c90b2bd1-ad84-4a20-90a2-bab467820996"> <id root="03811367-776c-454f-9954-9d02b496865f"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.2 Chronic Lymphocytic Leukemia </title> <text> <paragraph>The efficacy of CALQUENCE in patients with CLL was demonstrated in two randomized, controlled trials. The indication for CALQUENCE includes patients with SLL because it is the same disease.</paragraph> <paragraph> <content styleCode="italics">ELEVATE-TN</content> </paragraph> <paragraph>The efficacy of CALQUENCE was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of CALQUENCE in combination with obinutuzumab, CALQUENCE monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681). Patients 65 years of age or older or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) &gt; 6 or creatinine clearance of 30 to 69 mL/min were enrolled. The trial also required hepatic transaminases ≤ 3 times upper limit of normal (ULN) and total bilirubin ≤ 1.5 times ULN, and excluded patients with Richter’s transformation.</paragraph> <paragraph>Patients were randomized in a 1:1:1 ratio into 3 arms to receive:</paragraph> <list listType="unordered"> <item> <caption>•</caption>CALQUENCE plus obinutuzumab (CALQUENCE+G): CALQUENCE 100 mg was administered approximately every 12 hours starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.</item> <item> <caption>•</caption>CALQUENCE monotherapy: CALQUENCE 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity.</item> <item> <caption>•</caption>Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered intravenously on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 to 6. Chlorambucil 0.5 mg/kg was administered orally on Days 1 and 15 of Cycles 1 to 6. Each cycle was 28 days.</item> </list> <paragraph>Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or 1 versus 2), and geographic region. A total of 535 patients were randomized, 179 to CALQUENCE+G, 179 to CALQUENCE monotherapy, and 177 to GClb. The overall median age was 70 years (range: 41 to 91 years), 47% had Rai stage III or IV disease, 14% had 17p deletion or TP53 mutation, 63% of patients had an unmutated IGVH, and 18% had 11q deletion. Baseline demographic and disease characteristics were similar between treatment arms.</paragraph> <paragraph>Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0 to 40.8 months). Efficacy results are presented in Table 10. The Kaplan-Meier curves for PFS are shown in Figure 1.</paragraph> <table ID="_RefID0ECGBI" width="100%"> <caption>Table 10: Efficacy Results per IRC in Patients with CLL -- ITT population (ELEVATE-TN)</caption> <col width="39%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">CALQUENCE plus Obinutuzumab</content> </paragraph> <paragraph> <content styleCode="bold">N=179</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">CALQUENCE Monotherapy</content> </paragraph> <paragraph> <content styleCode="bold">N=179</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Obinutuzumab plus Chlorambucil</content> </paragraph> <paragraph> <content styleCode="bold">N=177</content> </paragraph> </td> </tr> <tr> <td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> <footnote ID="_Ref23776198">Per 2008 International Workshop on CLL (IWCLL) criteria.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14 (8)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>26 (15)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>93 (53)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>      PD, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>9 (5)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>20 (11)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>82 (46)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>      Death events, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5 (3)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6 (3)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>11 (6)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  Median (95% CI), months<footnote ID="_Ref23776241">Kaplan-Meier estimate.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NE</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NE (34, NE)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>22.6 (20, 28)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  HR<footnote ID="_Ref23776258">Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm.</footnote>(95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.10 (0.06, 0.17)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.20 (0.13, 0.30)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  p-value<footnote ID="_Ref23776275">Based on a stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the O’Brien-Fleming method. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>&lt; 0.0001</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>&lt; 0.0001</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td colspan="4" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Response Rate</content> <footnoteRef IDREF="_Ref23776198"/> <content styleCode="bold"> (CR + CRi + nPR + PR)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  ORR, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>168 (94)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>153 (86)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>139 (79)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>(89, 97)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>(80, 90)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>(72, 84)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  p-value<footnote ID="_Ref23776324">Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>&lt; 0.0001</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.0763</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  CR, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>23 (13)</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>8 (5)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  CRi, n (%)</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>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  nPR, n (%)</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>2 (1)</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>  PR, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>143 (80)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>150 (84)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>128 (72)</paragraph> </td> </tr> <tr> <td colspan="4" styleCode="Botrule " valign="top"> <paragraph>ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 1: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN</content> <renderMultiMedia ID="id-135269643" referencedObject="ID_79ddfbf6-648f-4782-8fe7-18a4ca3be880"/> </paragraph> <paragraph>With a median follow-up of 28.3 months, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event.</paragraph> <paragraph> <content styleCode="italics">ASCEND</content> </paragraph> <paragraph>The efficacy of CALQUENCE in patients with relapsed or refractory CLL was based upon a multicenter, randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory CLL after at least 1 prior systemic therapy. The trial excluded patients with transformed disease, prolymphocytic leukemia, or previous treatment with venetoclax, a Bruton tyrosine kinase inhibitor, or a phosphoinositide-3 kinase inhibitor.</paragraph> <paragraph>Patients were randomized in a 1:1 ratio to receive either:</paragraph> <list listType="unordered"> <item> <caption>•</caption>CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, or</item> <item> <caption>•</caption>Investigator’s choice:<list listType="unordered"> <item> <caption>•</caption>Idelalisib plus a rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with 8 infusions of a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.</item> <item> <caption>•</caption>Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles.</item> </list> </item> </list> <paragraph>Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or 1 versus 2), and number of prior therapies (1 to 3 versus ≥ 4). Of 310 patients total, 155 were assigned to CALQUENCE monotherapy, 119 to IR, and 36 to BR. The median age overall was 67 years (range: 32 to 90 years), 42% had Rai stage III or IV disease, 28% had 17p deletion or TP53 mutation, 78% of patients had an unmutated IGVH, and 27% had a 11q deletion. The CALQUENCE arm had a median of 1 prior therapy (range 1-8), with 47% having at least 2 prior therapies. The investigator’s choice arm had a median of 2 prior therapies (range 1-10), with 57% having at least 2 prior therapies.</paragraph> <paragraph>In the CALQUENCE arm, the median treatment duration was 15.7 months, with 94% of patients treated for at least 6 months and 86% of patients treated for at least 1 year. In the investigator’s choice arm, the median treatment duration was 8.4 months, with 59% of patients treated for at least 6 months and 37% treated for at least 1 year.</paragraph> <paragraph>Efficacy was based on PFS as assessed by an IRC, with a median follow-up of 16.1 months (range 0.03 to 22.4 months). Efficacy results are presented in Table 11. The Kaplan-Meier curve for PFS is shown in Figure 2. There was no statistically significant difference in overall response rates between the two treatment arms.</paragraph> <table ID="_RefID0E2RBI" width="100%"> <caption>Table 11: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL – ITT Population (ASCEND)</caption> <col width="39%"/> <col width="31%"/> <col width="31%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">CALQUENCE Monotherapy</content> <br/> <content styleCode="bold">N=155</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Investigator’s Choice of Idelalisib + Rituximab Product or Bendamustine + Rituximab Product</content> <br/> <content styleCode="bold">N=155</content> </th> </tr> </thead> <tbody> <tr> <td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> <footnote ID="_Ref23838113">Per 2008 IWCLL criteria.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  Number of events, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>27 (17)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>68 (44)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>      Disease progression, n </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>59</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>      Death, n </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>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  Median (95% CI), months<footnote ID="_Ref23838302">Kaplan-Meier estimate</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NE (NE, NE)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16.5 (14.0, 17.1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  HR (95% CI)<footnote ID="_Ref23838326">Based on a stratified Cox-Proportional-Hazards model</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.31 (0.20, 0.49)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  P-value<footnote ID="_Ref23838348">Based on a stratified Log-rank test. The pre-specified type I error rate (α) for this interim analysis is 0.012 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary </footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>&lt; 0.0001</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Response Rate (CR + CRi + nPR + PR)</content> <footnoteRef IDREF="_Ref23838113"/> <footnote ID="_Ref23838391">Through a hierarchical testing procedure, the difference in ORR was not statistically significant, based on a Cochran-Mantel Haenzel test with adjustment for randomization stratification factors. </footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  ORR, n (%)<footnoteRef IDREF="_Ref23838391"/> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>126 (81)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>117 (75) </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  (95% CI) </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>(74, 87) </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>(68, 82) </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  CR, n (%)</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>2 (1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  CRi, n (%)</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>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  nPR, n (%)</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>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>  PR, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>126 (81)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>115 (74)</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Botrule " valign="top"> <paragraph>ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response </paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND</content> <renderMultiMedia ID="id382138970" referencedObject="ID_88bc681c-f192-444f-b9ad-b9917feeff4b"/> </paragraph> <paragraph>With a median follow up of 16.1 months, median overall survival was not reached in either arm, with fewer than 11% of patients experiencing an event.</paragraph> </text> <effectiveTime value="20191122"/> <component> <observationMedia ID="ID_79ddfbf6-648f-4782-8fe7-18a4ca3be880"> <text>Figure 1</text> <value mediaType="image/jpeg"> <reference value="figure_1.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_88bc681c-f192-444f-b9ad-b9917feeff4b"> <text>Figure 2</text> <value mediaType="image/jpeg"> <reference value="figure_2.jpg"/> </value> </observationMedia> </component> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_bdfa53f2-d189-4dfb-828a-5ff9cf77dcca"> <id root="7ea1aaf5-3a88-4795-89cd-3432e920d6dd"/> <code code="34069-5" codeSystem="2.16.840.1.113883.6.1" displayName="HOW SUPPLIED SECTION"/> <title>16 HOW SUPPLIED/STORAGE AND HANDLING </title> <text> <paragraph> <content styleCode="underline">How Supplied</content> </paragraph> <table width="100%"> <col width="23%"/> <col width="45%"/> <col width="32%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Pack Size</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Contents</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">NDC Number</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>60-count bottle</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Bottle containing 60 capsules</paragraph> <paragraph>100 mg, hard gelatin capsules with yellow body and blue cap, marked in black ink with ‘ACA 100 mg’</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>0310-0512-60</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Storage</content> </paragraph> <paragraph>Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].</paragraph> </text> <effectiveTime value="20191122"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_a48c67c8-6ec5-45dd-8e8f-99dbed672c9c"> <id root="1b569db1-fa46-484b-a7e7-e75d479b4ce0"/> <code code="34076-0" codeSystem="2.16.840.1.113883.6.1" displayName="INFORMATION FOR PATIENTS SECTION"/> <title>17 PATIENT COUNSELING INFORMATION </title> <text> <paragraph>Advise the patient to read the FDA-approved patient labeling (Patient Information).</paragraph> <paragraph> <content styleCode="underline">Serious and Opportunistic Infections</content> </paragraph> <paragraph>Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection <content styleCode="italics">[see <linkHtml href="#ID_a4c950e2-42fd-447e-9d4a-ea48d372a53f">Warnings and Precautions (5.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Hemorrhage</content> </paragraph> <paragraph>Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries <content styleCode="italics">[see <linkHtml href="#ID_76c626fd-a938-4c7d-a620-957d6afcaca7">Warnings and Precautions (5.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Cytopenias</content> </paragraph> <paragraph>Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE <content styleCode="italics">[see <linkHtml href="#ID_77b0700d-b56a-499d-8550-6b11b73f6425">Warnings and Precautions (5.3)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Second Primary Malignancies</content> </paragraph> <paragraph>Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE, including skin cancer and other solid tumors. Advise patients to use sun protection <content styleCode="italics">[see <linkHtml href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">Warnings and Precautions (5.4)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Atrial Fibrillation and Flutter</content> </paragraph> <paragraph>Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath <content styleCode="italics">[see <linkHtml href="#ID_b13613ac-a265-4264-9e98-65d552d22e92">Warnings and Precautions (5.5)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Pregnancy Complication</content> </paragraph> <paragraph>CALQUENCE may cause fetal harm and dystocia. Advise women to avoid becoming pregnant during treatment and for at least 1 week after the last dose of CALQUENCE <content styleCode="italics">[see <linkHtml href="#ID_cf4be055-4786-457c-8934-4b05fafa7114">Use in Specific Populations (8.3)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Lactation</content> </paragraph> <paragraph>Advise females not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose <content styleCode="italics">[see <linkHtml href="#ID_0d455326-8dc0-4c3d-8d1e-0a74f652160a">Use in Specific Populations (8.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Dosing Instructions</content> </paragraph> <paragraph>Instruct patients to take CALQUENCE orally twice daily, about 12 hours apart. CALQUENCE may be taken with or without food. Advise patients that CALQUENCE capsules should be swallowed whole with a glass of water, without being opened, broken, or chewed <content styleCode="italics">[see <linkHtml href="#ID_1d2f0370-6594-4e65-addb-1bb7725a3e86">Dosage and Administration (2.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Missed Dose</content> </paragraph> <paragraph>Advise patients that if they miss a dose of CALQUENCE, they may still take it up to 3 hours after the time they would normally take it. If more than 3 hours have elapsed, they should be instructed to skip that dose and take their next dose of CALQUENCE at the usual time. Warn patients they should not take extra capsules to make up for the dose that they missed <content styleCode="italics">[see <linkHtml href="#ID_1d2f0370-6594-4e65-addb-1bb7725a3e86">Dosage and Administration (2.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Drug Interactions</content> </paragraph> <paragraph>Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins and herbal products <content styleCode="italics">[see <linkHtml href="#ID_aa417f83-52b8-48cc-aabd-390d4a2f1f74">Drug Interactions (7)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="bold">Distributed by:</content> </paragraph> <paragraph>AstraZeneca Pharmaceuticals LP</paragraph> <paragraph>Wilmington, DE 19850</paragraph> <paragraph>CALQUENCE is a registered trademark of the AstraZeneca group of companies.</paragraph> <paragraph>©AstraZeneca 2019</paragraph> </text> <effectiveTime value="20191122"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_fb779867-edf0-413f-bc9b-48463d5d931b"> <id root="7a583784-153f-40f7-bba2-808a0df9769c"/> <code code="42230-3" codeSystem="2.16.840.1.113883.6.1" displayName="SPL PATIENT PACKAGE INSERT SECTION"/> <text> <table width="100%"> <col width="44%"/> <col width="56%"/> <tbody> <tr> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">PATIENT INFORMATION</content> </paragraph> <paragraph> <content styleCode="bold">CALQUENCE^® (KAL-kwens)</content> </paragraph> <paragraph> <content styleCode="bold">(acalabrutinib)</content> </paragraph> <paragraph> <content styleCode="bold">Capsules</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What is CALQUENCE?</content> </paragraph> <paragraph>CALQUENCE is a prescription medicine used to treat adults with:</paragraph> <list listType="unordered"> <item> <caption>•</caption>Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.</item> <item> <caption>•</caption>Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).</item> </list> <paragraph>It is not known if CALQUENCE is safe and effective in children.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.</item> <item> <caption>•</caption>have bleeding problems.</item> <item> <caption>•</caption>have or had heart rhythm problems.</item> <item> <caption>•</caption>have an infection.</item> <item> <caption>•</caption>have or had liver problems, including hepatitis B virus (HBV) infection.</item> <item> <caption>•</caption>are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).<list listType="unordered"> <item> <caption>•</caption>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with CALQUENCE</item> <item> <caption>•</caption>Females who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for at least 1 week after the last dose of CALQUENCE.</item> </list> </item> <item> <caption>•</caption>are breastfeeding or plan to breastfeed. It is not known if CALQUENCE passes into your breast milk. Do not breastfeed during treatment with CALQUENCE and for at least 2 weeks after your final dose of CALQUENCE.</item> </list> <paragraph> <content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking CALQUENCE with certain other medications may affect how CALQUENCE works and can cause side effects. Especially tell your healthcare provider if you take a blood thinner medicine.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I take CALQUENCE?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Take CALQUENCE exactly as your healthcare provider tells you to take it.</item> <item> <caption>•</caption>Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.</item> <item> <caption>•</caption>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.</item> <item> <caption>•</caption>Take CALQUENCE 2 times a day (about 12 hours apart).</item> <item> <caption>•</caption>Take CALQUENCE with or without food.</item> <item> <caption>•</caption>Swallow CALQUENCE capsules whole with a glass of water. Do not open, break, or chew capsules.</item> <item> <caption>•</caption>If you need to take an antacid medicine, take it either 2 hours before or 2 hours after you take CALQUENCE.</item> <item> <caption>•</caption>If you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE 2 hours before the acid reducer medicine.</item> <item> <caption>•</caption>If you miss a dose of CALQUENCE, take it as soon as you remember. If it is more than 3 hours past your usual dosing time, skip the missed dose and take your next dose of CALQUENCE at your regularly scheduled time. Do not take an extra dose to make up for a missed dose.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">What are the possible side effects of CALQUENCE?</content> </paragraph> <paragraph> <content styleCode="bold">CALQUENCE may cause serious side effects, including:</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Serious infections </content>can happen during treatment with CALQUENCE and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection, including fever, chills, or flu-like symptoms.</item> <item> <caption>•</caption> <content styleCode="bold">Bleeding problems (hemorrhage)</content> can happen during treatment with CALQUENCE and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:</item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>blood in your stools or black stools (looks like tar)</item> <item> <caption>•</caption>pink or brown urine</item> <item> <caption>•</caption>unexpected bleeding, or bleeding that is severe or you cannot control</item> <item> <caption>•</caption>vomit blood or vomit that looks like coffee grounds</item> <item> <caption>•</caption>cough up blood or blood clots</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>dizziness</item> <item> <caption>•</caption>weakness</item> <item> <caption>•</caption>confusion</item> <item> <caption>•</caption>changes in your speech</item> <item> <caption>•</caption>headache that lasts a long time</item> <item> <caption>•</caption>bruising or red or purple skin marks</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="bold">Decrease in blood cell counts. </content>Decreased blood counts (white blood cells, platelets, and red blood cells) are common with CALQUENCE, but can also be severe. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with CALQUENCE.</item> <item> <caption>•</caption> <content styleCode="bold">Second primary cancers. </content>New cancers have happened in people during treatment with CALQUENCE, including cancers of the skin or other organs. Your healthcare provider will check you for skin cancers during treatment with CALQUENCE. Use sun protection when you are outside in sunlight.</item> <item> <caption>•</caption> <content styleCode="bold">Heart rhythm problems (atrial fibrillation and atrial flutter) </content>have happened in people treated with CALQUENCE. Tell your healthcare provider if you have any of the following signs or symptoms: </item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>fast or irregular heartbeat</item> <item> <caption>•</caption>dizziness</item> <item> <caption>•</caption>feeling faint</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>chest discomfort</item> <item> <caption>•</caption>shortness of breath</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">The most common side effects of CALQUENCE include:</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>headache</item> <item> <caption>•</caption>diarrhea</item> <item> <caption>•</caption>muscle and joint pain</item> </list> </td> <td styleCode="Rrule Botrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>upper respiratory tract infection</item> <item> <caption>•</caption>bruising</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>These are not all of the possible side effects of CALQUENCE. </paragraph> <paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I store CALQUENCE?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).</item> <item> <caption> </caption> <content styleCode="bold">Keep CALQUENCE and all medicines out of the reach of children.</content> </item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General information about the safe and effective use of CALQUENCE.</content> </paragraph> <paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CALQUENCE for a condition for which it was not prescribed. Do not give CALQUENCE to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about CALQUENCE that is written for health professionals.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What are the ingredients in CALQUENCE?</content> </paragraph> <paragraph> <content styleCode="bold">Active ingredient: </content>acalabrutinib</paragraph> <paragraph> <content styleCode="bold">Inactive ingredients: </content>silicified microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate. </paragraph> <paragraph>Capsule shell contains: gelatin, titanium dioxide, yellow iron oxide, FD&amp;C Blue 2, and black ink.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850</paragraph> <paragraph>CALQUENCE is a registered trademark of the AstraZeneca group of companies.</paragraph> <paragraph>©AstraZeneca XXXX</paragraph> <paragraph>For more information, go to www.CALQUENCE.com or call 1-800-236-9933.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">This Patient Information has been approved by the U.S. Food and Drug Administration.                      Revised: 11/2019</content> </paragraph> </text> <effectiveTime value="20191122"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_691cf42f-7df1-440f-9e55-33777a5dd2b2"> <id root="7690becb-7236-4e67-bc20-4c241084222a"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>PACKAGE/LABEL PRINCIPAL DISPLAY PANEL </title> <text> <paragraph>NDC 0310-0512-60                                 60 capsules</paragraph> <paragraph>CALQUENCE^® </paragraph> <paragraph>(acalabrutinib) capsules</paragraph> <paragraph>100 mg</paragraph> <paragraph> <content styleCode="bold">Rx only</content> </paragraph> <paragraph>Manufactured for:</paragraph> <paragraph>AstraZeneca Pharmaceuticals LP</paragraph> <paragraph>Wilmington, DE 19850</paragraph> <paragraph>By: AstraZeneca AB</paragraph> <paragraph>SE-151 85 Södertàlje, Sweden</paragraph> <paragraph>Product of Switzerland</paragraph> <paragraph>Astra Zeneca</paragraph> <renderMultiMedia ID="id440881228" referencedObject="ID_080445e1-b219-45c3-887a-531bb036de14"/> </text> <effectiveTime value="20191122"/> <component> <observationMedia ID="ID_080445e1-b219-45c3-887a-531bb036de14"> <text>Calquence 100 mg bottle label</text> <value mediaType="image/jpeg"> <reference value="Calquence_100_mg_bottle_label.jpg"/> </value> </observationMedia> </component> </section>