Hyperqbank

acalabrutinib

CALQUENCE

100

ORAL

CAPSULE

Marketed

[ "acalabrutinib" ]

Product Monograph

CALQUENCE

100

ORAL

TABLET

Marketed

[ "acalabrutinib (acalabrutinib maleate)" ]

Product Monograph

[ "Bruton Tyrosine Kinase (BTK) Inhibitors" ]

[ "Antineoplastics" ]

[ "Antineoplastic Agents" ]

dd4835ef-e1bc-4997-a399-1ffa2556fbfe

CALQUENCE- acalabrutinib capsule, gelatin coated

1 Indications And Usage

1.1 Previously Untreated Mantle Cell Lymphoma

CALQUENCE in combination with bendamustine and rituximab is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).

1.2 Previously Treated Mantle Cell Lymphoma

CALQUENCE is indicated for the treatment of adult patients with MCL who have received at least one prior therapy.

1.3 Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

2 Dosage And Administration

2.1 Recommended Dosage

CALQUENCE Administration Instructions

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.

CALQUENCE as Monotherapy

For patients with MCL, CLL, or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

CALQUENCE in Combination with Bendamustine and Rituximab

For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

Start CALQUENCE on Day 1 of Cycle 1 (each cycle is 28 days) and administer until disease progression or unacceptable toxicity. Administer bendamustine 90 mg/m2 on Days 1 and 2 and rituximab 375 mg/m2 on Day 1 of Cycle 1 and continue for a total of 6 cycles. Patients achieving a response (PR or CR) after the first 6 cycles may receive maintenance rituximab on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30 [see Clinical Studies (14.1)].

CALQUENCE in Combination with Obinutuzumab

For patients with previously untreated CLL or SLL, the recommended dosage 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.

2.2 Recommended Dosage For Hepatic Impairment

Avoid administration of CALQUENCE in patients with severe hepatic impairment.

Dosage modifications are not required for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Recommended Dosage For Drug Interactions

Dose Modifications for Use with CYP3A Inhibitors or Inducers

These are described in Table 1 [see Drug Interactions (7)].

<div class="scrollingtable"><table width="100%"> <caption> Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers </caption> <col width="11%"/> <col width="21%"/> <col width="68%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> CYP3A </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Co-administered Drug </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Recommended CALQUENCE use </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> Inhibition </td><td class="Botrule Lrule Rrule" valign="middle"> Strong CYP3A inhibitor </td><td class="Botrule Lrule Rrule" valign="middle"> Avoid concomitant use. If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> Moderate CYP3A inhibitor </td><td class="Botrule Lrule Rrule" valign="middle"> 100 mg once daily. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> Induction </td><td class="Botrule Lrule Rrule" valign="middle"> Strong CYP3A inducer </td><td class="Botrule Lrule Rrule" valign="middle"> Avoid concomitant use. If these inducers cannot be avoided, increase CALQUENCE dose to 200 mg approximately every 12 hours. </td> </tr> </tbody> </table></div>

Concomitant Use with Gastric Acid Reducing Agents

Proton Pump Inhibitors: Avoid concomitant use [see Drug Interactions (7)].

H2-Receptor Antagonists: Take CALQUENCE 2 hours before taking a H2-receptor antagonist [see Drug Interactions (7)].

Antacids: Separate dosing by at least 2 hours [see Drug Interactions (7)].

2.4 Dose Modifications For Adverse Reactions

Recommended dosage modifications are provided in Table 2 and 3.

<div class="scrollingtable"><table width="100%"> <caption> Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab </caption> <col width="26%"/> <col width="19%"/> <col width="55%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Event </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Adverse Reaction Occurrence </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Dose Modification (Starting dose = 100 mg approximately every 12 hours) </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, </td><td class="Botrule Lrule Rrule" valign="middle"> First and Second </td><td class="Botrule Lrule Rrule" valign="middle"> Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours. </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days </td><td class="Botrule Lrule Rrule" valign="middle"> Third </td><td class="Botrule Lrule Rrule" valign="middle"> Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="middle"> Fourth </td><td class="Botrule Lrule Rrule" valign="middle"> Discontinue CALQUENCE. </td> </tr> <tr class="Last"> <td class="Botrule" colspan="3" valign="top"> Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR </caption> <col width="22%"/> <col width="19%"/> <col width="59%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Adverse Reaction</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Severitya</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours)</th> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> Neutropeniab[see <a href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">Warnings and Precautions (5.4)</a>] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Absolute neutrophil count less than 0.5 x 109 /L for greater than 7 days </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2, resume CALQUENCE at starting dosage. Upon 2nd or 3rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 4th occurrence. For bendamustineb: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m2.d,e </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Thrombocytopeniaf[see <a href="#ID_b731a8ae-14dc-4432-a8b8-a1f9d429493b">Warnings and Precautions (5.4)</a>] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Platelet count 25 to 50 x 109/L with clinically significant bleeding or platelet count less than 25 x 109/L </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Consider discontinuing CALQUENCE at 3rd occurrence. For bendamustinef: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Non‑hematologic adverse reactions [see <a href="#ID_5c2015ae-ca1d-4f69-8fa1-21502ea47bf3">Warnings and Precautions (5)</a>] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or higher </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 3rd occurrence of Grade 4 toxicity. For Grade 3 toxicity, consider the risks and benefits of continuing CALQUENCE. For bendamustine: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b For neutropenia with ANC less than 1 x 109/L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m2 may be appropriate in certain circumstances. c Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. d Consider use of myeloid growth factors before bendamustine dosage reduction. e Consider discontinuing bendamustine if additional dosage reduction is required. f For thrombocytopenia, a platelet count below 50 x 109/L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding. </td> </tr> </tbody> </table></div>

Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

3 Dosage Forms And Strengths

Capsules:100 mg acalabrutinib size 1 hard gelatine capsules, with a yellow body and blue cap, marked in black ink with ‘ACA 100 mg’.

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4 Contraindications

None.

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5 Warnings And Precautions

5.1 Serious And Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 32% of 1,764 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (19% of all patients, including pneumonia in 9%) [see Adverse Reactions (6.1)]. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 2.7% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci 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.

5.2 Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.4% of patients, with fatal hemorrhage occurring in 0.2% of 1,764 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 40% of patients [see Adverse Reactions (6.1)].

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 7% of patients taking CALQUENCE without antithrombotic agents and 4% 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.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.3 Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (26%), platelets decreased (10%), hemoglobin decreased (10%), and absolute lymphocyte count decreased (10%) in patients treated with CALQUENCE alone or in combination with obinutuzumab; Grade 4 neutropenia developed in 14% [see Adverse Reactions (6.1)].

Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)].

5.4 Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 18% of 1,764 patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 10% of patients, followed by other solid tumors in 9% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1%). Monitor patients for the development of second cancers and advise protection from sun exposure.

5.5 Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.6% of 1,764 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients [see Adverse Reactions (6.1)]. Grade 3 or higher ventricular arrhythmia events were reported in 0.6% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias 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.

5.6 Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

6 Adverse Reactions

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 1,764 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 1,256 patients in 9 trials, and CALQUENCE combinations in 508 patients in 3 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 80% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1,764 patients, excluding laboratory abnormalities, were diarrhea (37%), upper respiratory tract infection (36%), headache (35%), musculoskeletal pain (33%), lower respiratory tract infection (32%), and fatigue (32%). The most common grade 3 or 4 laboratory abnormalities (≥10%) were absolute neutrophil count decreased (31%), absolute lymphocyte count decreased (23%), platelets decreased (11%), and hemoglobin decreased (10%).

Previously Untreated Mantle Cell Lymphoma

The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without BR) in patients with MCL [see Clinical Studies (14.1)].

ECHO

The safety of CALQUENCE in combination with bendamustine and rituximab (CALQUENCE plus BR) was evaluated in 297 patients with previously untreated MCL in ECHO [see Clinical Studies (14.1)]. The trial enrolled patients with previously untreated MCL, ≥ 65 years of age with no intention for transplant, total bilirubin ≤ 1.5 × ULN, AST or ALT ≤ 2.5 × ULN, and estimated creatinine clearance of > 50 mL/min. Patients received 6 cycles (as 28-day cycles) of CALQUENCE 100 mg orally twice daily (n = 297) or placebo (n = 297) in combination with bendamustine and rituximab. Patients then received CALQUENCE 100 mg orally twice daily or placebo continuously until progressive disease or unacceptable toxicity, with 12 additional dosages of rituximab every other cycle up to Cycle 30.

The median duration of treatment with CALQUENCE was 28.6 months. A total of 171 (57.6%) patients were treated with CALQUENCE for ˃ 24 months and 122 (41.1%) patients were treated for ˃ 36 months.

Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR. Serious adverse reactions reported in ≥ 2% of patients were pneumonia (23%; includes COVID-19 pneumonia), COVID-19 (20%; includes COVID-19 pneumonia), pyrexia (6%), second primary malignancy (7%), rash (3.4%), febrile neutropenia (3.4%), atrial fibrillation (3%), sepsis (2.7%), and anemia (2.4%). Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including COVID-19 (6%; includes COVID-19 pneumonia), pneumonia (1%), sepsis (0.3%), second primary malignancy (0.7%), and pneumonitis (0.3%).

Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in > 10% included infections, cytopenias, rashes, and gastrointestinal toxicity. Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥ 4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia.

Table 4 and Table 5 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> Table 4: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Body Systems Adverse Reactions* </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> CALQUENCE plus BR N = 297 </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> Placebo plus BR N = 297 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or 4 (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or 4 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Skin and subcutaneous tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Rasha </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 47 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Infections </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Covid-19b </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 38 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Upper respiratory tract infectionc </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 30 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ….Pneumoniad </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Gastrointestinal disorder </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 26 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> General disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigue </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 32 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Pyrexia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 24 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Edema </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Nervous system disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Headache </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dizziness </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Respiratory, thoracic and mediastinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Cough </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dyspnea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Neoplasms </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Secondary primary malignancye </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Arthralgia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Vascular disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemorrhagef </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> *Excludes laboratory terms. a Includes rash, dermatitis, and other related terms. b Includes the following fatal adverse reactions: n=24 for COVID-19. c Includes upper respiratory tract infection, sinusitis, pharyngitis, and related terms. d Includes pneumonia, terms containing pneumonia, and related infections. COVID-19 pneumonia is represented under both Pneumonia and COVID-19. e Includes terms related to malignant neoplasms including cutaneous neoplasms. f Includes all terms containing hematoma or hemorrhage and related terms indicative of bleeding. </td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus BR included bruising, abdominal pain, atrial fibrillation or flutter, and tumor lysis syndrome.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> Table 5: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> Laboratory Abnormality </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> CALQUENCE plus BRa </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> Placebo plus BRa </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> All grade (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or 4 (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> All grade (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or 4 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Hematologic Abnormalities </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Lymphocytes decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 98 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 87 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 97 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 89 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemoglobin decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 80 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 65 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Neutrophils decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 76 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 56 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 77 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 51 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Platelets decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 69 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 60 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Chemistry Abnormalities </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> AST increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 53 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 50 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Uric acid increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 45 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 45 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ALT increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 44 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 41 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Potassium increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 38 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Creatinine increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Phosphate decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 36 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.4 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 30 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Potassium decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 23 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Bilirubin increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> a The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with a baseline value and at least one post-treatment value. </td> </tr> </tbody> </table></div>

Grade 4 laboratory abnormalities in > 15% of patients treated with CALQUENCE plus BR include absolute lymphocyte count decreased (26%), absolute neutrophil count decreased (36%), and uric acid increased (17%).

Previously Treated Mantle Cell Lymphoma

ACE-LY-004

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 [see Clinical Studies (14.2)]. 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.

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.

Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Tables 6 and 7 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.

<div class="scrollingtable"><table width="100%"> <caption> Table 6: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004 </caption> <col width="34%"/> <col width="34%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Per NCI CTCAE version 4.03.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Rash: Includes all terms containing ‘rash’</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> Body System Adverse Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> CALQUENCE Monotherapy N=124 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Nervous system disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Headache </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 39 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Gastrointestinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 3.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Abdominal pain </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> General disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigue </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Myalgia </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 21 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Skin and subcutaneous tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Bruising<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 21 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Rash<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Vascular disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemorrhage<a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 8 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Respiratory, thoracic and mediastinal disorders </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Epistaxis </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 6 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> Table 7: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004 </caption> <col width="37%"/> <col width="37%"/> <col width="27%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> Hematologic Adverse Reactions<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> CALQUENCE Monotherapy N=124 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemoglobin decreased </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 46 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 10 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Platelets decreased </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 44 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Neutrophils decreased </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 36 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td> </tr> </tbody> </table></div>

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

Chronic Lymphocytic Leukemia

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 [see Clinical Studies (14.3)].

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.

ELEVATE-TN

The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL [see Clinical Studies (14.2)].

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.

ELEVATE-TN

Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity. Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6 cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every 12 hours until disease progression or unacceptable toxicity. The trial required age ≥ 65 years of age or 18 to < 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases ≤ 3 times ULN and total bilirubin ≤ 1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.

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.

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%).

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.

Tables 8 and 9 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 8: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN) </caption> <col width="25%"/> <col width="23%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Per NCI CTCAE version 4.03</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>Includes any adverse reactions involving infection or febrile neutropenia</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>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</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Upper respiratory tract infection, nasopharyngitis and sinusitis</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">¶</a> </dt> <dd>Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">#</a> </dt> <dd>Derived from adverse reactions and laboratory data</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">Þ</a> </dt> <dd>Includes neutropenia, neutrophil count decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">ß</a> </dt> <dd>Includes anemia, red blood cell count decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">à</a> </dt> <dd>Includes thrombocytopenia, platelet count decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">è</a> </dt> <dd>Includes lymphocytosis, lymphocyte count increased, and related laboratory data</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">ð</a> </dt> <dd>Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">ø</a> </dt> <dd>Includes asthenia, fatigue, and lethargy</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">ý</a> </dt> <dd>Includes bruise, contusion, and ecchymosis</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">£</a> </dt> <dd>Includes rash, dermatitis, and other related terms</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">¥</a> </dt> <dd>Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> Body System Adverse Reaction<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> CALQUENCE plus Obinutuzumab N=178 </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> CALQUENCE Monotherapy N=179 </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> Obinutuzumab plus Chlorambucil N=169 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> <dl> <dt> </dt> <dd> Infections </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Infection<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 69 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 22<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 65 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 14<a class="Sup" href="#footnote-8">‡</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 46 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 13<a class="Sup" href="#footnote-8">‡</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Upper respiratory tract infection<a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 39 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2.8 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 35 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Lower respiratory tract infection<a class="Sup" href="#footnote-10" name="footnote-reference-10">¶</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 24 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 8 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 4.5 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Urinary tract infection</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2.8 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 5 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> <dl> <dt> </dt> <dd> Blood and lymphatic system disorders<a class="Sup" href="#footnote-11" name="footnote-reference-11">#</a> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Neutropenia<a class="Sup" href="#footnote-12" name="footnote-reference-12">Þ</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 53 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 23 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 78 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 50 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Anemia<a class="Sup" href="#footnote-13" name="footnote-reference-13">ß</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 52 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 53 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 10 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 54 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 14 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Thrombocytopenia<a class="Sup" href="#footnote-14" name="footnote-reference-14">à</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 51 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 32 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 3.4 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 61 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 16 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Lymphocytosis<a class="Sup" href="#footnote-15" name="footnote-reference-15">è</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 16 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Nervous system disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Headache</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 39 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dizziness</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Gastrointestinal disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diarrhea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 39 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 4.5 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 35 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 21 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Nausea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 22 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Musculoskeletal and connective tissue disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Musculoskeletal pain<a class="Sup" href="#footnote-16" name="footnote-reference-16">ð</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2.2 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 32 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 16 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Arthralgia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 22 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 16 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 4.7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> General disorders and administration site conditions </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Fatigue<a class="Sup" href="#footnote-17" name="footnote-reference-17">ø</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 34 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2.2 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 23 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 24 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Skin and subcutaneous tissue disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Bruising<a class="Sup" href="#footnote-18" name="footnote-reference-18">ý</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>31</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>21</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Rash<a class="Sup" href="#footnote-19" name="footnote-reference-19">£</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>26</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.2</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>25</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>9</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.6</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Vascular disorders </dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hemorrhage<a class="Sup" href="#footnote-20" name="footnote-reference-20">¥</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 6 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> </tbody> </table></div>

Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included:

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 9: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN) </caption> <col width="21%"/> <col width="21%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Laboratory Abnormality<a class="Sup" href="#footnote-21" name="footnote-reference-21">*</a><a class="Sup" href="#footnote-22" name="footnote-reference-22">†</a></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE plus Obinutuzumab N=178</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE Monotherapy N=179</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Obinutuzumab plus Chlorambucil N=169</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-21" name="footnote-21">*</a> </dt> <dd>Per NCI CTCAE version 4.03</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">†</a> </dt> <dd>Excludes electrolytes</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Uric acid increase </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 22 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 22 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 37 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> ALT increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 30 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 7 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 20 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 1.1 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 36 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 6 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> AST increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 38 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 5 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 17 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 60 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 8 </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> Bilirubin increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 11 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0.6 </td> </tr> </tbody> </table></div>

Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

ASCEND

The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized, open-label study (ASCEND) [see Clinical Studies (14.3)]. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times ULN, total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients having an absolute neutrophil count < 500/µL, platelet count < 30,000/µL, prothrombin time or activated partial thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement for strong CYP3A inhibitors or inducers. Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonist.

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.

In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

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.

Selected adverse reactions are described in Table 10 and non-hematologic laboratory abnormalities are described in Table 11. These tables reflect exposure to CALQUENCE with median duration of 15.7 months with 94% of patients on treatment for greater than 6 months and 86% of patients on treatment for greater than 12 months. The median duration of exposure to idelalisib was 11.5 months with 72% of patients on treatment for greater than 6 months and 48% of patients on treatment for greater than 12 months. Eighty-three percent of patients completed 6 cycles of bendamustine and rituximab product.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 10: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND) </caption> <col width="26%"/> <col width="22%"/> <col width="11%"/> <col width="11%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-23" name="footnote-23">*</a> </dt> <dd>Per NCI CTCAE version 4.03</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">†</a> </dt> <dd>Includes any adverse reactions involving infection or febrile neutropenia</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">‡</a> </dt> <dd>Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">§</a> </dt> <dd>Upper respiratory tract infection, rhinitis and nasopharyngitis</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">¶</a> </dt> <dd>Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">#</a> </dt> <dd>Derived from adverse reaction and laboratory data</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">Þ</a> </dt> <dd>Includes neutropenia, neutrophil count decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">ß</a> </dt> <dd>Includes anemia, red blood cell decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-31" name="footnote-31">à</a> </dt> <dd>Includes thrombocytopenia, platelet count decreased, and related laboratory data</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">è</a> </dt> <dd>Includes lymphocytosis, lymphocyte count increased and related laboratory data</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">ð</a> </dt> <dd>Includes colitis, diarrhea, and enterocolitis</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">ø</a> </dt> <dd>Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis</dd> <dt> <a href="#footnote-reference-35" name="footnote-35">ý</a> </dt> <dd>Includes asthenia, fatigue, and lethargy</dd> <dt> <a href="#footnote-reference-36" name="footnote-36">£</a> </dt> <dd>Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"> Body System Adverse Reaction<a class="Sup" href="#footnote-23" name="footnote-reference-23">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> CALQUENCE N=154 </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> Idelalisib plus Rituximab Product N=118 </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> Bendamustine plus Rituximab Product N=35 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> Grade ≥ 3 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> <dl> <dt> </dt> <dd> Infections </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Infection<a class="Sup" href="#footnote-24" name="footnote-reference-24">†</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>56</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15<a class="Sup" href="#footnote-25" name="footnote-reference-25">‡</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>65</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>28<a class="Sup" href="#footnote-25">‡</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>49</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>11</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Upper respiratory tract infection<a class="Sup" href="#footnote-26" name="footnote-reference-26">§</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>29</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.9</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>26</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>3.4</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>17</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.9</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Lower respiratory tract infection<a class="Sup" href="#footnote-27" name="footnote-reference-27">¶</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>23</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>26</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>14</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> <dl> <dt> </dt> <dd> Blood and lymphatic system disorders<a class="Sup" href="#footnote-28" name="footnote-reference-28">#</a> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Neutropenia<a class="Sup" href="#footnote-29" name="footnote-reference-29">Þ</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>48</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>23</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>79</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>53</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>80</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>40</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Anemia<a class="Sup" href="#footnote-30" name="footnote-reference-30">ß</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>47</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>45</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>8</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>57</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>17</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Thrombocytopenia<a class="Sup" href="#footnote-31" name="footnote-reference-31">à</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>33</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>41</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>13</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>54</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Lymphocytosis<a class="Sup" href="#footnote-32" name="footnote-reference-32">è</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>26</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>19</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>23</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>18</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.9</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.9</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Nervous system disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Headache</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>22</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Gastrointestinal disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diarrhea<a class="Sup" href="#footnote-33" name="footnote-reference-33">ð</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>18</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.3</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>49</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>25</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>14</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Vascular disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hemorrhage<a class="Sup" href="#footnote-34" name="footnote-reference-34">ø</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>16</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.3</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>5</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.7</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.9</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> General disorders </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Fatigue<a class="Sup" href="#footnote-35" name="footnote-reference-35">ý</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.9</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>13</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0.8</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>31</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>6</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <dl> <dt> </dt> <dd> Musculoskeletal and connective tissue disorders </dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Musculoskeletal Pain<a class="Sup" href="#footnote-36" name="footnote-reference-36">£</a> </dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.3</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>15</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>1.7</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2.9</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>0</dd> </dl> </td> </tr> </tbody> </table></div>

Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included:

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 11: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND) </caption> <col width="23%"/> <col width="23%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Laboratory Abnormality<a class="Sup" href="#footnote-37" name="footnote-reference-37">*</a></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE N=154</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Idelalisib plus Rituximab Product N=118</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Bendamustine plus Rituximab Product N=35</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-37" name="footnote-37">*</a> </dt> <dd>Excludes electrolytes</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Uric acid increase </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 23 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 23 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> ALT increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 15 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 1.9 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 59 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 23 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 26 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 2.9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> AST increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0.6 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 48 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 31 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 2.9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> Bilirubin increase </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 13 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 1.3 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 16 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 1.7 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 26 </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 11 </td> </tr> <tr class="Last"> <td class="Botrule" colspan="7" valign="middle"> Per NCI CTCAE version 5 </td> </tr> </tbody> </table></div>

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CALQUENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 Drug Interactions

<div class="scrollingtable"><table width="100%"> <col width="19%"/> <col width="30%"/> <col width="51%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> Strong CYP3A Inhibitors </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Clinical Impact </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>Co-administration of CALQUENCE with a strong CYP3A inhibitor (itraconazole) increased acalabrutinib plasma concentrations [see <a href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</a>].</dd> <dt>•</dt> <dd>Increased acalabrutinib concentrations may result in increased toxicity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>Avoid co-administration of strong CYP3A inhibitors with CALQUENCE.</dd> <dt>•</dt> <dd>Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see <a href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">Recommended Dosage for Drug Interactions (2.3)</a>].</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Moderate CYP3A Inhibitors </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Clinical Impact </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [see <a href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</a>]. </dd> <dt>•</dt> <dd>Increased acalabrutinib concentrations may result in increased toxicity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> Strong CYP3A Inducers </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Clinical Impact </td><td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <dl> <dt>•</dt> <dd>Co-administration of CALQUENCE with a strong CYP3A inducer (rifampin) decreased acalabrutinib plasma concentrations [see <a href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</a>].</dd> <dt>•</dt> <dd>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <dl> <dt>•</dt> <dd>Avoid co-administration of strong CYP3A inducers with CALQUENCE.</dd> <dt>•</dt> <dd>If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> Gastric Acid Reducing Agents </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> Clinical Impact </td><td class="Botrule Lrule Rrule" colspan="2" valign="middle"> <dl> <dt>•</dt> <dd>Co-administration of CALQUENCE with a proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations [see <a href="#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f">Clinical Pharmacology (12.3)</a>].</dd> <dt>•</dt> <dd>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</dd> <dt>•</dt> <dd>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).</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> Prevention or Management </td><td class="Botrule Lrule Rrule" valign="middle"> Antacids </td><td class="Botrule Lrule Rrule" valign="middle"> Separate dosing by at least 2 hours [see <a href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">Recommended Dosage for Drug Interactions (2.3)</a>]. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> H2-receptor antagonists </td><td class="Botrule Lrule Rrule" valign="middle"> Take CALQUENCE 2 hours before taking the H2-receptor antagonist [see <a href="#ID_9ba703c9-7b46-4239-9ed4-061924b069b9">Recommended Dosage for Drug Interactions (2.3)</a>]. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> Proton pump inhibitors </td><td class="Botrule Lrule Rrule" valign="middle"> Avoid co-administration. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"19%\"/>\n<col width=\"30%\"/>\n<col width=\"51%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n\nStrong CYP3A Inhibitors\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nClinical Impact\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Co-administration of CALQUENCE with a strong CYP3A inhibitor (itraconazole) increased acalabrutinib plasma concentrations [see <a href=\"#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f\">Clinical Pharmacology (12.3)</a>].</dd>\n<dt>•</dt>\n<dd>Increased acalabrutinib concentrations may result in increased toxicity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nPrevention or Management\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Avoid co-administration of strong CYP3A inhibitors with CALQUENCE.</dd>\n<dt>•</dt>\n<dd>Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see <a href=\"#ID_9ba703c9-7b46-4239-9ed4-061924b069b9\">Recommended Dosage for Drug Interactions (2.3)</a>].</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nModerate CYP3A Inhibitors\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nClinical Impact\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [see <a href=\"#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f\">Clinical Pharmacology (12.3)</a>].\n</dd>\n<dt>•</dt>\n<dd>Increased acalabrutinib concentrations may result in increased toxicity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nPrevention or Management\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"middle\">\n\nStrong CYP3A Inducers\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nClinical Impact\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<dl>\n<dt>•</dt>\n<dd>Co-administration of CALQUENCE with a strong CYP3A inducer (rifampin) decreased acalabrutinib plasma concentrations [see <a href=\"#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f\">Clinical Pharmacology (12.3)</a>].</dd>\n<dt>•</dt>\n<dd>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nPrevention or Management\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<dl>\n<dt>•</dt>\n<dd>Avoid co-administration of strong CYP3A inducers with CALQUENCE.</dd>\n<dt>•</dt>\n<dd>If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"middle\">\n\nGastric Acid Reducing Agents\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n\nClinical Impact\n\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<dl>\n<dt>•</dt>\n<dd>Co-administration of CALQUENCE with a proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations [see <a href=\"#ID_7e085cea-9439-4c36-9305-3c4a71a4e52f\">Clinical Pharmacology (12.3)</a>].</dd>\n<dt>•</dt>\n<dd>Decreased acalabrutinib concentrations may reduce CALQUENCE activity.</dd>\n<dt>•</dt>\n<dd>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).</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" rowspan=\"3\" valign=\"middle\">\n\nPrevention or Management\n\n</td><td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nAntacids\n</td><td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nSeparate dosing by at least 2 hours [see <a href=\"#ID_9ba703c9-7b46-4239-9ed4-061924b069b9\">Recommended Dosage for Drug Interactions (2.3)</a>].\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nH2-receptor antagonists\n</td><td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nTake CALQUENCE 2 hours before taking the H2-receptor antagonist [see <a href=\"#ID_9ba703c9-7b46-4239-9ed4-061924b069b9\">Recommended Dosage for Drug Interactions (2.3)</a>].\n\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nProton pump inhibitors\n</td><td class=\"Botrule Lrule Rrule\" valign=\"middle\">\nAvoid co-administration. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.\n</td>\n</tr>\n</tbody>\n</table></div>" }

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

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 (see Data). Advise pregnant women of the potential risk to a fetus.

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.

Data

Animal Data

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.

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.

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.

8.2 Lactation

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.

8.3 Females And Males Of Reproductive Potential

CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.

Contraception

Females

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.

8.4 Pediatric Use

The safety and efficacy of CALQUENCE in pediatric patients have not been established.

8.5 Geriatric Use

CLL and Previously Treated MCL

Of the 1,467 CALQUENCE-treated patients with CLL or relapsed or refractory MCL in clinical trials, 977 (67%) were 65 years of age or older, and 328 (22%) were 75 years of age or older. Among patients 65 years of age or older, 74% had Grade 3 or higher adverse reactions and 58% had serious adverse reactions. Among patients younger than age 65, 61% had Grade 3 or higher adverse reactions and 39% had serious adverse reactions. No clinically relevant differences in efficacy were observed between patients ≥ 65 years and younger.

Previously Untreated MCL

Of the 297 CALQUENCE-treated patients with previously untreated MCL, 214 (72%) were 65 to 74 years of age and 83 (28%) were 75 years of age and older. No clinically relevant differences in safety or efficacy were observed between patients ages 65 to 74 years and those who were 75 years of age and older.

8.6 Hepatic Impairment

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 [see Recommended Dosage for Hepatic Impairment (2.2) and Clinical Pharmacology (12.3)].

11 Description

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.

{ "type": "p", "children": [], "text": "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." }

The chemical structure of acalabrutinib is shown below:

{ "type": "p", "children": [], "text": "The chemical structure of acalabrutinib is shown below:" }

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.

{ "type": "p", "children": [], "text": "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." }

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&C Blue 2 and is imprinted with edible black ink.

{ "type": "p", "children": [], "text": "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&C Blue 2 and is imprinted with edible black ink." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

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.

12.2 Pharmacodynamics

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.

Cardiac Electrophysiology

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).

12.3 Pharmacokinetics

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.

Absorption

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.

Effect of Food

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 Cmax decreased by 73% and Tmax was delayed 1-2 hours.

Distribution

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.

Elimination

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.

Metabolism

Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro 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.

Excretion

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.

Specific Populations

Age, Race, and Body Weight

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.

Renal Impairment

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 < 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis.

Hepatic Impairment

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).

Drug Interaction Studies

Effect of CYP3A Inhibitors on Acalabrutinib

Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.

Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax and AUC approximately 2- to 3-fold.

Effect of CYP3A Inducers on Acalabrutinib

Co-administration with a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects.

Gastric Acid Reducing Agents

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%.

In Vitro Studies

Metabolic Pathways

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.

Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.

Based on in vitro data and PBPK modeling, no interaction with CYP substrates is expected at clinically relevant concentrations.

Drug Transporter Systems

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.

Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K at clinically relevant concentrations.

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.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with acalabrutinib.

Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay.

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.

14 Clinical Studies

14.1 Previously Untreated Mantle Cell Lymphoma

ECHO

The efficacy of CALQUENCE in patients with previously untreated MCL was evaluated in a randomized, double blind, placebo controlled, multicenter study (ECHO; NCT02972840). The study enrolled 598 patients who were ≥ 65 years of age and who had no intention for transplant. The study excluded patients with total bilirubin > 1.5 × upper limit of normal (ULN), AST or ALT > 2.5 × ULN, or estimated creatinine clearance of ≤ 50 mL/min. Patients were randomized in a 1:1 ratio to receive CALQUENCE plus bendamustine and rituximab (CALQUENCE plus BR) or placebo plus BR. Dosing for both arms was administered in 28-day cycles as follows:

Patients on the control arm received the same regimen but placebo in lieu of CALQUENCE. Crossover to CALQUENCE monotherapy was permitted for patients in the placebo plus BR arm at disease progression.

Of all patients randomized, the median age was 71 years (range: 65-86); 71% were male; 78% were White, 16% Asian, 0.5% were Black or African American. In total, 80% had classic histology of MCL, 7.7% had blastoid MCL, and 5.5% had pleomorphic MCL. The simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score was low in 33%, intermediate in 43%, and high in 24% of patients. A total of 38% of patients had tumor bulk ≥ 5 cm and 86% had Ann Arbor stage IV disease.

The major efficacy outcome was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) using the Lugano Classification. Efficacy results are presented in Table 12. The Kaplan-Meier curves for PFS are shown in Figure 1. At this prespecified interim analysis, the median follow-up for PFS was 49.8 months in both arms.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> Table 12. Efficacy Results in Patients with Previously Untreated MCL in ECHO </caption> <col width="39%"/> <col width="31%"/> <col width="28%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-38" name="footnote-38">*</a> </dt> <dd>Stratified by randomization stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]).</dd> <dt> <a href="#footnote-reference-39" name="footnote-39">†</a> </dt> <dd>Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI).</dd> <dt> <a href="#footnote-reference-40" name="footnote-40">‡</a> </dt> <dd>Estimated based on stratified log-rank test for p-value, with an alpha level of 0.039 derived by the O’Brien-Fleming method.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Outcomes per IRC </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE plus BR N= 299 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Placebo plus BR N= 299 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Progression-Free Survival<a class="Sup" href="#footnote-38" name="footnote-reference-38">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Median (95% CI), months</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 66.4 (55.1, NE) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 49.6 (36.0, 64.1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>HR<a class="Sup" href="#footnote-39" name="footnote-reference-39">†</a> (95% CI)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.73 (0.57, 0.94) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>P-value<a class="Sup" href="#footnote-40" name="footnote-reference-40">‡</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.016 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (ORR) (CR + PR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>ORR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 272 (91) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 263 (88) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>95% CI</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 87, 94 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 84, 91 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 199 (67) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 160 (54) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>PR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 73 (24) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 103 (34) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.220 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> HR = hazard ratio, CR = complete response, PR = partial response, NE – not evaluable </td> </tr> </tbody> </table></div>

Figure 1. Kaplan-Meier Curve of IRC-Assessed PFS in Patients with Previously Untreated MCL in ECHO

At the time of the PFS analysis, the median overall survival had not been reached in either arm with a total of 203 deaths: 97 (32%) patients in the CALQUENCE plus BR arm and 106 (35%) patients in the placebo plus BR arm had died.

14.2 Previously Treated Mantle Cell Lymphoma

ACE-LY-004

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.

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 Mantle Cell Lymphoma International Prognostic Index (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.

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.

<div class="scrollingtable"><table width="100%"> <caption> Table 13: Efficacy Results in Patients with MCL in Trial LY-004 </caption> <col width="43%"/> <col width="25%"/> <col width="32%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-41" name="footnote-41">*</a> </dt> <dd>Per 2014 Lugano Classification.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Investigator Assessed N=124 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Independent Review Committee (IRC) Assessed N=124 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (ORR)<a class="Sup" href="#footnote-41" name="footnote-reference-41">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ORR (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 81 [73, 87] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 80 [72, 87] </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Complete Response (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 40 [31, 49] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 40 [31, 49] </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Partial Response (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 41 [32, 50] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 40 [32, 50] </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Duration of Response (DoR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median DoR in months [range] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> NE [1+ to 20+] </td><td align="center" class="Botrule Lrule Rrule" valign="top"> NE [0+ to 20+] </td> </tr> <tr class="Last"> <td class="Botrule" colspan="3" valign="top"> CI= Confidence Interval; NE=Not Estimable; + indicates censored observations </td> </tr> </tbody> </table></div>

The median time to best response was 1.9 months.

Lymphocytosis

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.

14.3 Chronic Lymphocytic Leukemia

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.

ELEVATE-TN

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) > 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.

Patients were randomized in a 1:1:1 ratio into 3 arms to receive:

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.

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.

<div class="scrollingtable"><table width="100%"> <caption> Table 14: 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%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-42" name="footnote-42">*</a> </dt> <dd>Per 2008 International Workshop on CLL (IWCLL) criteria.</dd> <dt> <a href="#footnote-reference-43" name="footnote-43">†</a> </dt> <dd>Kaplan-Meier estimate.</dd> <dt> <a href="#footnote-reference-44" name="footnote-44">‡</a> </dt> <dd>Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm.</dd> <dt> <a href="#footnote-reference-45" name="footnote-45">§</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-46" name="footnote-46">¶</a> </dt> <dd>Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE plus Obinutuzumab N=179 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE Monotherapy N=179 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Obinutuzumab plus Chlorambucil N=177 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> Progression-Free Survival<a class="Sup" href="#footnote-42" name="footnote-reference-42">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Number of events (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 14 (8) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 26 (15) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 93 (53) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> PD, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 9 (5) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 20 (11) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 82 (46) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Death events, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 5 (3) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 6 (3) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 11 (6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median (95% CI), months<a class="Sup" href="#footnote-43" name="footnote-reference-43">†</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> NE </td><td align="center" class="Botrule Lrule Rrule" valign="top"> NE (34, NE) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 22.6 (20, 28) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> HR<a class="Sup" href="#footnote-44" name="footnote-reference-44">‡</a>(95% CI) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.10 (0.06, 0.17) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.20 (0.13, 0.30) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> p-value<a class="Sup" href="#footnote-45" name="footnote-reference-45">§</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> Overall Response Rate<a class="Sup" href="#footnote-42">*</a> (CR + CRi + nPR + PR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ORR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 168 (94) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 153 (86) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 139 (79) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> (95% CI) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> (89, 97) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> (80, 90) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> (72, 84) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> p-value<a class="Sup" href="#footnote-46" name="footnote-reference-46">¶</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0.0763 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 23 (13) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 8 (5) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CRi, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> nPR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2 (1) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 3 (2) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> PR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 143 (80) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 150 (84) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 128 (72) </td> </tr> <tr class="Last"> <td class="Botrule" colspan="4" valign="top"> 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. </td> </tr> </tbody> </table></div>

Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN

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.

ASCEND

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.

Patients were randomized in a 1:1 ratio to receive either:

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.

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.

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.

<div class="scrollingtable"><table width="100%"> <caption> Table 15: 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 class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">CALQUENCE Monotherapy N=155</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Investigator’s Choice of Idelalisib + Rituximab Product or Bendamustine + Rituximab Product N=155</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-47" name="footnote-47">*</a> </dt> <dd>Per 2008 IWCLL criteria.</dd> <dt> <a href="#footnote-reference-48" name="footnote-48">†</a> </dt> <dd>Kaplan-Meier estimate</dd> <dt> <a href="#footnote-reference-49" name="footnote-49">‡</a> </dt> <dd>Based on a stratified Cox-Proportional-Hazards model</dd> <dt> <a href="#footnote-reference-50" name="footnote-50">§</a> </dt> <dd>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</dd> <dt> <a href="#footnote-reference-51" name="footnote-51">¶</a> </dt> <dd>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.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> Progression-Free Survival<a class="Sup" href="#footnote-47" name="footnote-reference-47">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Number of events, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 27 (17) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 68 (44) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Disease progression, n </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 59 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Death, n </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 8 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median (95% CI), months<a class="Sup" href="#footnote-48" name="footnote-reference-48">†</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> NE (NE, NE) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 16.5 (14.0, 17.1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> HR (95% CI)<a class="Sup" href="#footnote-49" name="footnote-reference-49">‡</a> </td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> 0.31 (0.20, 0.49) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> P-value<a class="Sup" href="#footnote-50" name="footnote-reference-50">§</a> </td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> < 0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (CR + CRi + nPR + PR)<a class="Sup" href="#footnote-47">*</a><a class="Sup" href="#footnote-51" name="footnote-reference-51">¶</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ORR, n (%)<a class="Sup" href="#footnote-51">¶</a> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 126 (81) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 117 (75) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> (95% CI) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> (74, 87) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> (68, 82) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 2 (1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CRi, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> nPR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> PR, n (%) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 126 (81) </td><td align="center" class="Botrule Lrule Rrule" valign="top"> 115 (74) </td> </tr> <tr class="Last"> <td class="Botrule" colspan="3" valign="top"> 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 </td> </tr> </tbody> </table></div>

Figure 3: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND

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.

16 How Supplied/Storage And Handling

How Supplied

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<div class="scrollingtable"><table width="100%"> <col width="13%"/> <col width="74%"/> <col width="13%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Pack Size </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Contents </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NDC Number </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> 60-count bottle </td><td class="Botrule Lrule Rrule" valign="top"> Bottle containing 60 capsules 100 mg, hard gelatin capsules with yellow body and blue cap, marked in black ink with ‘ACA 100 mg’ </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> 0310-0512-60 </td> </tr> </tbody> </table></div>

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Storage

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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].

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17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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Serious and Opportunistic Infections

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Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1)]." }

Hemorrhage

{ "type": "p", "children": [], "text": "\nHemorrhage\n" }

Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)]." }

Cytopenias

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Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [see Warnings and Precautions (5.3)]." }

Second Primary Malignancies

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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 [see Warnings and Precautions (5.4)].

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Cardiac Arrhythmias

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Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)]." }

Hepatotoxicity, including Drug Induced Liver Injury:

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Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during CALQUENCE treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during CALQUENCE treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.6)].\n" }

Pregnancy Complication

{ "type": "p", "children": [], "text": "\nPregnancy Complication\n" }

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 [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "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 [see Use in Specific Populations (8.3)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise females not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise females not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose [see Use in Specific Populations (8.2)]." }

Dosing Instructions

{ "type": "p", "children": [], "text": "\nDosing Instructions\n" }

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 [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "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 [see Dosage and Administration (2.1)]." }

Missed Dose

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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 [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "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 [see Dosage and Administration (2.1)]." }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins and herbal products [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins and herbal products [see Drug Interactions (7)]." }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

AstraZeneca Pharmaceuticals LP

{ "type": "p", "children": [], "text": "AstraZeneca Pharmaceuticals LP" }

Wilmington, DE 19850

{ "type": "p", "children": [], "text": "Wilmington, DE 19850" }

CALQUENCE is a registered trademark of the AstraZeneca group of companies.

{ "type": "p", "children": [], "text": "CALQUENCE is a registered trademark of the AstraZeneca group of companies." }

©AstraZeneca 2025

{ "type": "p", "children": [], "text": "©AstraZeneca 2025" }

Patient Information

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> PATIENT INFORMATION CALQUENCE® (KAL-kwens) (acalabrutinib) Capsules </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> What is CALQUENCE? CALQUENCE is a prescription medicine used to treat adults with: <dl> <dt>•</dt> <dd>Mantle cell lymphoma (MCL) in combination with bendamustine and rituximab in people who have not had prior treatment for MCL and who cannot receive a type of stem cell transplant that uses their own blood stem cells (autologous hematopoietic stem cell transplantation).</dd> <dt>•</dt> <dd>have Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.</dd> <dt>•</dt> <dd>have Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)</dd> </dl> It is not known if CALQUENCE is safe and effective in children. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you: <dl> <dt>•</dt> <dd>have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.</dd> <dt>•</dt> <dd>have bleeding problems.</dd> <dt>•</dt> <dd>have or had heart rhythm problems.</dd> <dt>•</dt> <dd>have an infection.</dd> <dt>•</dt> <dd>have or had liver problems, including hepatitis B virus (HBV) infection.</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).</dd> <dt>o</dt> <dd>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with CALQUENCE</dd> <dt>o</dt> <dd>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.</dd> <dt>•</dt> <dd>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.</dd> </dl> Tell your healthcare provider about all the medicines you take, 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. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> How should I take CALQUENCE? <dl> <dt>•</dt> <dd>Take CALQUENCE exactly as your healthcare provider tells you to take it.</dd> <dt>•</dt> <dd>Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.</dd> <dt>•</dt> <dd>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.</dd> <dt>•</dt> <dd>Take CALQUENCE 2 times a day (about 12 hours apart).</dd> <dt>•</dt> <dd>Take CALQUENCE with or without food.</dd> <dt>•</dt> <dd>Swallow CALQUENCE capsules whole with a glass of water. Do not open, break, or chew capsules.</dd> <dt>•</dt> <dd>If you need to take an antacid medicine, take it either 2 hours before or 2 hours after you take CALQUENCE.</dd> <dt>•</dt> <dd>If you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE 2 hours before the acid reducer medicine.</dd> <dt>•</dt> <dd>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.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> What are the possible side effects of CALQUENCE? CALQUENCE may cause serious side effects, including: <dl> <dt>•</dt> <dd> Serious infections have happened in people treated 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.</dd> <dt>•</dt> <dd> Bleeding problems (hemorrhage) have happened in people treated 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:</dd> <dt>o</dt> <dd>blood in your stools or black stools (looks like tar)</dd> <dt>o</dt> <dd>pink or brown urine</dd> <dt>o</dt> <dd>unexpected bleeding, or bleeding that is severe or you cannot control</dd> <dt>o</dt> <dd>vomit blood or vomit that looks like coffee grounds</dd> <dt>o</dt> <dd>cough up blood or blood clots</dd> <dt>o</dt> <dd>dizziness</dd> <dt>o</dt> <dd>weakness</dd> <dt>o</dt> <dd>confusion</dd> <dt>o</dt> <dd>changes in your speech</dd> <dt>o</dt> <dd>headaches that lasts a long time</dd> <dt>o</dt> <dd>bruising or red or purple skin marks</dd> <dt>•</dt> <dd> Decrease in blood cell counts. 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.</dd> <dt>•</dt> <dd> Second primary cancers. 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.</dd> <dt>•</dt> <dd> Heart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, have happened in people treated with CALQUENCE, and can be serious or lead to death. Tell your healthcare provider if you have any of the following signs or symptoms:</dd> <dt>o</dt> <dd>fast or irregular heartbeat</dd> <dt>o</dt> <dd>dizziness</dd> <dt>o</dt> <dd>feeling faint</dd> <dt>o</dt> <dd>chest discomfort</dd> <dt>o</dt> <dd>shortness of breath</dd> <dt>•</dt> <dd> Liver problems. Liver problems have happened in people treated with CALQUENCE, and can be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE.</dd> </dl> The most common side effects of CALQUENCE include: <dl> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>upper respiratory tract infection</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>muscle and joint pain</dd> <dt>•</dt> <dd>lower respiratory infection</dd> <dt>•</dt> <dd>tiredness</dd> </dl> These are not all of the possible side effects of CALQUENCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> How should I store CALQUENCE? <dl> <dt>•</dt> <dd>Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).</dd> </dl> Keep CALQUENCE and all medicines out of the reach of children. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> General information about the safe and effective use of CALQUENCE. 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. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> What are the ingredients in CALQUENCE? Active ingredient: acalabrutinib Inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate. Capsule shell contains: gelatin, titanium dioxide, yellow iron oxide, FD&C Blue 2, and black ink. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 CALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2025 For more information, go to <a href="http://www.TRADENAME.com">www.CALQUENCE.com</a> or call 1-800-236-9933. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nPATIENT INFORMATION\n\n\nCALQUENCE® (KAL-kwens)\n\n\n(acalabrutinib)\n\n\nCapsules\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nWhat is CALQUENCE?\n\nCALQUENCE is a prescription medicine used to treat adults with:\n<dl>\n<dt>•</dt>\n<dd>Mantle cell lymphoma (MCL) in combination with bendamustine and rituximab in people who have not had prior treatment for MCL and who cannot receive a type of stem cell transplant that uses their own blood stem cells (autologous hematopoietic stem cell transplantation).</dd>\n<dt>•</dt>\n<dd>have Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.</dd>\n<dt>•</dt>\n<dd>have Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)</dd>\n</dl>\nIt is not known if CALQUENCE is safe and effective in children.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nBefore taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you:\n\n<dl>\n<dt>•</dt>\n<dd>have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.</dd>\n<dt>•</dt>\n<dd>have bleeding problems.</dd>\n<dt>•</dt>\n<dd>have or had heart rhythm problems.</dd>\n<dt>•</dt>\n<dd>have an infection.</dd>\n<dt>•</dt>\n<dd>have or had liver problems, including hepatitis B virus (HBV) infection.</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).</dd>\n<dt>o</dt>\n<dd>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with CALQUENCE</dd>\n<dt>o</dt>\n<dd>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.</dd>\n<dt>•</dt>\n<dd>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.</dd>\n</dl>\n\nTell your healthcare provider about all the medicines you take, 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.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nHow should I take CALQUENCE?\n\n<dl>\n<dt>•</dt>\n<dd>Take CALQUENCE exactly as your healthcare provider tells you to take it.</dd>\n<dt>•</dt>\n<dd>Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.</dd>\n<dt>•</dt>\n<dd>Take CALQUENCE 2 times a day (about 12 hours apart).</dd>\n<dt>•</dt>\n<dd>Take CALQUENCE with or without food.</dd>\n<dt>•</dt>\n<dd>Swallow CALQUENCE capsules whole with a glass of water. Do not open, break, or chew capsules.</dd>\n<dt>•</dt>\n<dd>If you need to take an antacid medicine, take it either 2 hours before or 2 hours after you take CALQUENCE.</dd>\n<dt>•</dt>\n<dd>If you need to take certain other medicines called acid reducers (H-2 receptor blockers), take CALQUENCE 2 hours before the acid reducer medicine.</dd>\n<dt>•</dt>\n<dd>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.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nWhat are the possible side effects of CALQUENCE?\n\n\nCALQUENCE may cause serious side effects, including:\n\n<dl>\n<dt>•</dt>\n<dd>\nSerious infections have happened in people treated 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.</dd>\n<dt>•</dt>\n<dd>\nBleeding problems (hemorrhage) have happened in people treated 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:</dd>\n<dt>o</dt>\n<dd>blood in your stools or black stools (looks like tar)</dd>\n<dt>o</dt>\n<dd>pink or brown urine</dd>\n<dt>o</dt>\n<dd>unexpected bleeding, or bleeding that is severe or you cannot control</dd>\n<dt>o</dt>\n<dd>vomit blood or vomit that looks like coffee grounds</dd>\n<dt>o</dt>\n<dd>cough up blood or blood clots</dd>\n<dt>o</dt>\n<dd>dizziness</dd>\n<dt>o</dt>\n<dd>weakness</dd>\n<dt>o</dt>\n<dd>confusion</dd>\n<dt>o</dt>\n<dd>changes in your speech</dd>\n<dt>o</dt>\n<dd>headaches that lasts a long time</dd>\n<dt>o</dt>\n<dd>bruising or red or purple skin marks</dd>\n<dt>•</dt>\n<dd>\nDecrease in blood cell counts. 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.</dd>\n<dt>•</dt>\n<dd>\nSecond primary cancers. 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.</dd>\n<dt>•</dt>\n<dd>\nHeart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, have happened in people treated with CALQUENCE, and can be serious or lead to death. Tell your healthcare provider if you have any of the following signs or symptoms:</dd>\n<dt>o</dt>\n<dd>fast or irregular heartbeat</dd>\n<dt>o</dt>\n<dd>dizziness</dd>\n<dt>o</dt>\n<dd>feeling faint</dd>\n<dt>o</dt>\n<dd>chest discomfort</dd>\n<dt>o</dt>\n<dd>shortness of breath</dd>\n<dt>•</dt>\n<dd>\nLiver problems. Liver problems have happened in people treated with CALQUENCE, and can be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE.</dd>\n</dl>\n\nThe most common side effects of CALQUENCE include:\n\n<dl>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>upper respiratory tract infection</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>muscle and joint pain</dd>\n<dt>•</dt>\n<dd>lower respiratory infection</dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n</dl>\nThese are not all of the possible side effects of CALQUENCE. \nCall your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nHow should I store CALQUENCE?\n\n<dl>\n<dt>•</dt>\n<dd>Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n</dl>\n\nKeep CALQUENCE and all medicines out of the reach of children.\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nGeneral information about the safe and effective use of CALQUENCE.\n\nMedicines 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.\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nWhat are the ingredients in CALQUENCE?\n\n\nActive ingredient: acalabrutinib\n\nInactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate.\nCapsule shell contains: gelatin, titanium dioxide, yellow iron oxide, FD&C Blue 2, and black ink.\nDistributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850\nCALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2025\nFor more information, go to <a href=\"http://www.TRADENAME.com\">www.CALQUENCE.com</a> or call 1-800-236-9933.\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 1/2025

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Package/Label Principal Display Panel

NDC 0310-0512-60 60 capsules

{ "type": "p", "children": [], "text": "NDC 0310-0512-60 60 capsules" }

CALQUENCE®

{ "type": "p", "children": [], "text": "CALQUENCE®\n" }

(acalabrutinib) capsules

{ "type": "p", "children": [], "text": "(acalabrutinib) capsules" }

100 mg

{ "type": "p", "children": [], "text": "100 mg" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

AstraZeneca Pharmaceuticals LP

{ "type": "p", "children": [], "text": "AstraZeneca Pharmaceuticals LP" }

Wilmington, DE 19850

{ "type": "p", "children": [], "text": "Wilmington, DE 19850" }

By: AstraZeneca AB

{ "type": "p", "children": [], "text": "By: AstraZeneca AB" }

SE-151 85 Södertàlje, Sweden

{ "type": "p", "children": [], "text": "SE-151 85 Södertàlje, Sweden" }

Product of Switzerland

{ "type": "p", "children": [], "text": "Product of Switzerland" }

AstraZeneca

{ "type": "p", "children": [], "text": "AstraZeneca" }

b1409184-3267-4d8c-8f17-4e01f69828b1

CALQUENCE- acalabrutinib tablet, film coated

1 Indications And Usage

1.1 Previously Untreated Mantle Cell Lymphoma

1.2 Previously Treated Mantle Cell Lymphoma

CALQUENCE is indicated for the treatment of adult patients with MCL who have received at least one prior therapy.

1.3 Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

2 Dosage And Administration

2.1 Recommended Dosage

CALQUENCE Administration Instructions

Advise patients to swallow tablet whole with water. Advise patients not to chew, crush, dissolve, or cut the tablets. 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 tablets of CALQUENCE should not be taken to make up for a missed dose.

CALQUENCE as Monotherapy

For patients with MCL, CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

CALQUENCE in Combination with Bendamustine and Rituximab

For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

CALQUENCE in Combination with Obinutuzumab

2.2 Recommended Dosage For Drug Interactions

Dosage Modifications for Use with CYP3A Inhibitors or Inducers

These are described in Table 1 [see Drug Interactions (7)].

<div class="scrollingtable"><table width="100%"> <caption> Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers </caption> <col width="14%"/> <col width="30%"/> <col width="56%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> CYP3A </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Co-administered Drug </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Recommended CALQUENCE use </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> Inhibition </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Strong CYP3A inhibitor </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Avoid co-administration. If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Moderate CYP3A inhibitor </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Induction </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Strong CYP3A inducer </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Avoid co-administration. If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours. </td> </tr> </tbody> </table></div>

2.3 Dosage Modifications For Adverse Reactions

Recommended dosage modifications of are provided in Table 2 and 3.

<div class="scrollingtable"><table width="100%"> <caption> Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab </caption> <col width="32%"/> <col width="19%"/> <col width="49%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Event</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Adverse Reaction Occurrence</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Dosage Modification (Starting dose = 100 mg approximately every 12 hours)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> First and Second </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Third </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Fourth </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Discontinue CALQUENCE. </td> </tr> <tr class="Last"> <td colspan="3" valign="middle"> Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="454.25pt"> <caption> Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR </caption> <col width="21%"/> <col width="18%"/> <col width="56%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Adverse Reaction</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Severitya</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours)</th> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> Neutropeniab[see Warnings and Precautions (5.4)] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Absolute neutrophil count less than 0.5 x 109/L for greater than 7 days </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2, resume CALQUENCE at starting dosage. Upon 2nd or 3rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 4th occurrence. For bendamustineb: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m2.d,e </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Thrombocytopeniaf[see Warnings and Precautions (5.4)] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Platelet count 25 to 50 x 109/L with clinically significant bleeding or platelet count less than 25 x 109/L </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Consider discontinuing CALQUENCE at 3rd occurrence. For bendamustinef: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Non‑hematologic adverse reactions [see Warnings and Precautions (5)] </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Grade 3 or higher </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily.c Discontinue CALQUENCE at 3rd occurrence of Grade 4 toxicity. For Grade 3 toxicity, consider the risks and benefits of continuing CALQUENCE. For bendamustine: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m2.e </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b For neutropenia with ANC less than 1 x 109/L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m2 may be appropriate in certain circumstances. c Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. d Consider use of myeloid growth factors before bendamustine dosage reduction. e Consider discontinuing bendamustine if additional dosage reduction is required. f For thrombocytopenia, a platelet count below 50 x 109/L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding. </td> </tr> </tbody> </table></div>

Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

3 Dosage Forms And Strengths

Tablets:100 mg acalabrutinib, orange, oval, film-coated, biconvex, debossed with ‘ACA 100’ on one side and plain on the other.

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4 Contraindications

None.

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5 Warnings And Precautions

5.1 Serious And Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

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%) [see Adverse Reactions (6.1)]. 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, Pneumocystis jirovecii 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.

5.2 Hemorrhage

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 [see Adverse Reactions (6.1)].

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.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.3 Cytopenias

Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.3)].

5.4 Second Primary Malignancies

5.5 Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. 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 [see Adverse Reactions (6.1)]. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of 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.

5.6 Hepatotoxicity, Including Drug-Induced Liver Injury

6 Adverse Reactions

6.1 Clinical Trials Experience

Previously Untreated Mantle Cell Lymphoma

The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without BR) in patients with MCL [see Clinical Studies (14.1)].

ECHO

The median duration of treatment with CALQUENCE was 28.6 months. A total of 171 (57.6%) patients were treated with CALQUENCE for ˃ 24 months and 122 (41.1%) patients were treated for ˃ 36 months.

Table 4 and Table 5 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO.

<div class="scrollingtable"><table cellpadding="3pt" width="100%"> <caption> Table 4: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO </caption> <col width="36%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Body System Adverse Reactions*</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">CALQUENCE plus BR N = 297</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">Placebo plus BR N = 297</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Grade 3 or 4 (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Grade 3 or 4 (%)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Skin and subcutaneous tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Rasha </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 47 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Infections </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> COVID-19b </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 38 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Upper respiratory tract infectionc </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 30 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Pneumoniad </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Gastrointestinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 26 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> General disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigue </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 32 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Pyrexia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 24 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Edema </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Nervous system disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Headache </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dizziness </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Respiratory, thoracic and mediastinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Cough </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.3 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dyspnea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Neoplasms </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Secondary primary malignancye </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Arthralgia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Vascular disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemorrhagef </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> *Excludes laboratory terms. a Includes rash, dermatitis, and other related terms. </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> b Includes the following fatal adverse reactions: n=24 for COVID-19. </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> c Includes upper respiratory tract infection, sinusitis, pharyngitis, and related terms. </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> d Includes pneumonia, terms containing pneumonia, and related infections. COVID-19 pneumonia is represented under both Pneumonia and COVID-19. </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> e Includes terms related to malignant neoplasms including cutaneous neoplasms. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> f Includes all terms containing hematoma or hemorrhage and related terms indicative of bleeding. </td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus BR included bruising, abdominal pain, atrial fibrillation or flutter, and tumor lysis syndrome.

<div class="scrollingtable"><table cellpadding="3pt" width="100%"> <caption> Table 5: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO </caption> <col width="29%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <thead> <tr class="First"> <th align="center" class="Lrule Rrule Toprule" rowspan="2" valign="middle">Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">CALQUENCE plus BR</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">Placebo plus BR</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top">All grade (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Grade 3 or 4 (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">All grade (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Grade 3 or 4 (%)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> Hematologic Abnormalities </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Lymphocytes decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 98 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 87 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 97 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 89 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Hemoglobin decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 80 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 65 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Neutrophils decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 76 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 56 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 77 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 51 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Platelets decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 69 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 60 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> Chemistry Abnormalities </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> AST increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 53 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 50 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Uric acid increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 45 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 45 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> ALT increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 44 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 41 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Potassium increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 38 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Creatinine increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Phosphate decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 36 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.4 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 30 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.7 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Potassium decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 29 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 23 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Bilirubin increased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td> </tr> <tr class="Last"> <td colspan="5" valign="top"> a The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with a baseline value and at least one post-treatment value. </td> </tr> </tbody> </table></div>

Previously Treated Mantle Cell Lymphoma

ACE-LY-004

Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Tables 6 and 7 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.

<div class="scrollingtable"><table width="100%"> <caption> Table 6: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004 </caption> <col width="39%"/> <col width="30%"/> <col width="30%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Body System Adverse Reactions*</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE Monotherapy N=124</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Nervous system disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Headache </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 39 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Gastrointestinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Abdominal pain </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> General disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigue </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Myalgia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 21 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Skin and subcutaneous tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Bruisinga </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 21 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Rashb </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Vascular disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemorrhagec </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 8 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Respiratory, thoracic and mediastinal disorders </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Epistaxis </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> </tbody> </table></div>

*Per NCI CTCAE version 4.03.

a Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’.

b Rash: Includes all terms containing ‘rash’.

c Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’.

<div class="scrollingtable"><table width="100%"> <caption> Table 7: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY 004 </caption> <col width="41%"/> <col width="30%"/> <col width="30%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> Hematologic Adverse Reactions* </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> CALQUENCE Monotherapy N=124 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> All Grades (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Grade ≥ 3 (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Hemoglobin decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 46 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 10 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Platelets decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 44 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Neutrophils decreased </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 36 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td> </tr> </tbody> </table></div>

*Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.

Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.

Chronic Lymphocytic Leukemia

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.

ELEVATE-TN

Tables 8 and 9 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 8: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN) </caption> <col width="27%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Body System Adverse Reaction*</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom">CALQUENCE plus Obinutuzumab N=178</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom">CALQUENCE Monotherapy N=179</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom">Obinutuzumab plus Chlorambucil N=169</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> Infections </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Infection† </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 69 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 22‡ </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 65 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 14‡ </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 46 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 13‡ </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Upper respiratory tract infection§ </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 39 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.8 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 35 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 17 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Lower respiratory tract infectiona </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 24 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 8 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 18 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4.5 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Urinary tract infection </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.8 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 5 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="bottom"> Blood and lymphatic system disordersb </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Neutropeniac </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 53 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 23 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 13 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 78 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 50 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Anemiad </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 52 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 53 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 10 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 54 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Thrombocytopeniae </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 51 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 32 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 3.4 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 61 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Lymphocytosisf </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 11 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> Nervous system disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Headache </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 39 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Dizziness </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 12 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> Gastrointestinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 39 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4.5 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 35 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 21 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nausea </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 22 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Musculoskeletal paing </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 37 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.2 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 32 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.4 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Arthralgia </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 22 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 16 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 4.7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> General disorders and administration site conditions </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigueh </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 34 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.2 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 23 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 24 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.2 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> Skin and subcutaneous tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Bruisingi </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 31 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 21 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 5 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Rashj </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 26 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 2.2 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 25 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 9 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0.6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> Vascular disorders </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Hemorrhagek </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 1.7 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> </tbody> </table></div>

*Per NCI CTCAE version 4.03.

† Includes any adverse reactions involving infection or febrile neutropenia.

‡ 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.

§ Includes upper respiratory tract infection, nasopharyngitis and sinusitis.

a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection.

b Derived from adverse reaction and laboratory data.

c Includes neutropenia, neutrophil count decreased, and related laboratory data.

d Includes anemia, red blood cell count decreased, and related laboratory data.

e Includes thrombocytopenia, platelet count decreased, and related laboratory data.

f Includes lymphocytosis, lymphocyte count increased, and related laboratory data.

g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.

h Includes asthenia, fatigue, and lethargy.

i Includes bruise, contusion, and ecchymosis.

j Includes rash, dermatitis, and other related terms.

k Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis.

Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included:

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 9: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN) </caption> <col width="23%"/> <col width="13%"/> <col width="12%"/> <col width="13%"/> <col width="12%"/> <col width="13%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Laboratory Abnormality<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a><a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE plus Obinutuzumab N=178</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE Monotherapy N=179</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Obinutuzumab plus Chlorambucil N=169</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Per NCI CTCAE version 4.03</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Excludes electrolytes</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="middle"> Uric acid increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 29 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 29 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 22 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 22 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 37 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 37 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> ALT increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 30 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 7 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 20 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 1.1 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 36 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 6 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> AST increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 38 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 5 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 17 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 60 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 8 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> Bilirubin increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 13 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6 </td> </tr> </tbody> </table></div>

Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

ASCEND

* Per NCI CTCAE version 4.03.

† Includes any adverse reactions involving infection or febrile neutropenia.

‡ Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm.

§ Includes upper respiratory tract infection, rhinitis and nasopharyngitis.

a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection.

b Derived from adverse reaction and laboratory data.

c Includes neutropenia, neutrophil count decreased, and related laboratory data.

d Includes anemia, red blood cell decreased, and related laboratory data.

e Includes thrombocytopenia, platelet count decreased, and related laboratory data.

f Includes lymphocytosis, lymphocyte count increased and related laboratory data.

g Includes colitis, diarrhea, and enterocolitis.

h Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis.

i Includes asthenia, fatigue, and lethargy.

j Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain.

Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included:

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 11: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND) </caption> <col width="26%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Laboratory Abnormality<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">CALQUENCE N=154</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Idelalisib plus Rituximab Product N=118</th><th align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle">Bendamustine plus Rituximab Product N=35</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">All Grades (%)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle">Grade ≥ 3 (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Excludes electrolytes</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="middle"> Uric acid increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 23 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 23 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> ALT increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 15 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 1.9 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 59 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 23 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 26 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 2.9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> AST increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 13 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 48 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 13 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 31 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 2.9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> Bilirubin increase </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 13 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 1.3 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 16 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 1.7 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 26 </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> 11 </td> </tr> <tr class="Last"> <td colspan="7" valign="middle"> Per NCI CTCAE version 5 </td> </tr> </tbody> </table></div>

Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of CALQUENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 Drug Interactions

7.1 Effect Of Other Drugs On Calquence

<div class="scrollingtable"><table width="100%"> <col width="16%"/> <col width="84%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> Strong CYP3A Inhibitors </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> Clinical Effect </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Co-administration of CALQUENCE with a strong CYP3A inhibitor increased acalabrutinib plasma concentrations [see <a href="#ID_22a7a5d4-4d15-4766-a478-b80d69a685ae">Clinical Pharmacology (12.3)</a>]. Increased acalabrutinib concentrations may result in increased toxicity. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Avoid co-administration of CALQUENCE with strong CYP3A inhibitors. Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see <a href="#ID_febd1199-48f1-49ac-8b6d-8cd1ccefebab">Dosage and Administration (2.2)</a>]. </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> Moderate CYP3A Inhibitors </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> Clinical Effect </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentration [see <a href="#ID_22a7a5d4-4d15-4766-a478-b80d69a685ae">Clinical Pharmacology (12.3)</a>]. Increased acalabrutinib concentrations may result in increased toxicity. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule Toprule" valign="top"> Reduce the dosage of CALQUENCE when co-administered with a moderate CYP3A inhibitor [see <a href="#ID_febd1199-48f1-49ac-8b6d-8cd1ccefebab">Dosage and Administration (2.2)</a>]. </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="middle"> Strong CYP3A Inducers </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> Clinical Effect </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Co-administration of CALQUENCE with a strong CYP3A inducer decreased acalabrutinib plasma concentration [see <a href="#ID_22a7a5d4-4d15-4766-a478-b80d69a685ae">Clinical Pharmacology (12.3)</a>]. Decreased acalabrutinib concentrations may reduce CALQUENCE activity. </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> Prevention or Management </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Avoid co-administration of CALQUENCE with strong CYP3A inducers. If co-administration is unavoidable, increase the dosage of CALQUENCE [see <a href="#ID_febd1199-48f1-49ac-8b6d-8cd1ccefebab">Dosage and Administration (2.2)</a>]. </td> </tr> </tbody> </table></div>

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

Data

Animal Data

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.

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.

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.

8.2 Lactation

Risk Summary

8.3 Females And Males Of Reproductive Potential

CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for 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.

8.4 Pediatric Use

The safety and efficacy of CALQUENCE in pediatric patients have not been established.

8.5 Geriatric Use

CLL and Previously Treated MCL

Previously Untreated MCL

8.6 Hepatic Impairment

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The safety of CALQUENCE has not been evaluated in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

11 Description

CALQUENCE (acalabrutinib) is a kinase inhibitor. The molecular formula for acalabrutinib maleate is C26H23N7O2•C4H4O4.H2O, and the molecular weight is 599.59. The chemical name is 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate.

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The chemical structure of acalabrutinib is shown below:

{ "type": "p", "children": [], "text": "The chemical structure of acalabrutinib is shown below:" }

Acalabrutinib maleate is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6.

{ "type": "p", "children": [], "text": "Acalabrutinib maleate is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6." }

CALQUENCE tablets are for oral administration. Each tablet contains 100 mg of acalabrutinib (equivalent to 129 mg of acalabrutinib maleate). Inactive ingredients in the tablet core are low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet coating consists of copovidone, ferric oxide yellow, ferric oxide red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water and titanium dioxide.

{ "type": "p", "children": [], "text": "CALQUENCE tablets are for oral administration. Each tablet contains 100 mg of acalabrutinib (equivalent to 129 mg of acalabrutinib maleate). Inactive ingredients in the tablet core are low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet coating consists of copovidone, ferric oxide yellow, ferric oxide red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water and titanium dioxide." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Acalabrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (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.

12.2 Pharmacodynamics

In patients with B-cell malignancies dosed with acalabrutinib 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.

Cardiac Electrophysiology

At a dose 4 times the approved recommended dosage, CALQUENCE does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

Acalabrutinib and its active metabolite, ACP-5862, exposures increase proportionally with dose across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dosage) 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.

Absorption

The geometric mean absolute bioavailability of acalabrutinib was 25%. Median (min, max) time to peak plasma concentration (Tmax) of acalabrutinib and its active metabolite, ACP-5862 were 0.5 (0.2, 3.0) hours and 0.75 (0.5, 4.0) hours, respectively.

Effect of Food

In healthy subjects, administration of a single 100 mg dose of acalabrutinib 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 Cmax decreased by 54% and Tmax was delayed 1-2 hours.

Distribution

The geometric mean (% CV) steady-state volume of distribution (Vss) of acalabrutinib and its active metabolite, ACP-5862 was approximately 101 (52%) L and 67 (32%) L, respectively. Human plasma protein of acalabrutinib and its active metabolite, ACP-5862, were 97.5% and 98.6%, respectively. The mean blood-to-plasma ratio of acalabrutinib and its active metabolite, ACP-5862, was 0.8 and 0.7, respectively.

Elimination

The geometric mean (% CV) terminal elimination half-life (t1/2) of acalabrutinib and its active metabolite, ACP-5862, were 1.4 (50%) hours and 6.4 (37%) hours, respectively. The geometric mean (%CV) apparent oral clearance (CL/F) of acalabrutinib and its active metabolite, ACP-5862, were 71 (35%) L/hr and 13 (42%) L/hr, respectively.

Metabolism

Excretion

Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces (< 2% unchanged) and 12% of the dose was recovered in the urine (< 2% unchanged).

Specific Populations

There were no clinically significant differences in the pharmacokinetics of acalabrutinib and its active metabolite, ACP‑5862, based on age (32 to 90 years), sex, race (Caucasian, African American), body weight (40 to 149 kg), or mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2 and eGFR < 89 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). The effect of severe renal impairment (eGFR < 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis on the pharmacokinetics of acalabrutinib is unknown.

Patients with Hepatic Impairment

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inhibitors: Co-administration of acalabrutinib with itraconazole (strong CYP3A inhibitor) increase acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.

Moderate CYP3A Inhibitors: Co-administration of acalabrutinib with erythromycin (moderate CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), diltiazem (moderate CYP3A inhibitor) is predicted to increase acalabrutinib Cmax and AUC by approximately 2- to 3-fold.

Strong CYP3A Inducers: Co-administration of acalabrutinib with rifampin (strong CYP3A inducer) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects.

Acid-Reducing Agents: No clinically significant differences in the pharmacokinetics of acalabrutinib were observed when co-administered with rabeprazole (proton pump inhibitor).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Acalabrutinib is an inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but not CYP1A2, CYP2B6, CYP2C19, or CYP2D6. Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, but not CYP1A2, CYP2B6, CYP2D6, or CYP3A4/5. Acalabrutinib is an inducer of CYP1A2, CYP2B6, and CYP3A4. Acalabrutinib’s active metabolite, ACP-5862, is an inducer of CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Acalabrutinib and its active metabolite, ACP‑5862, are not inhibitors of UGT1A1 or UGT2B7.

Transporter System: Acalabrutinib is an inhibitor of breast cancer resistance protein (BCRP), but not multidrug and toxin extrusion protein 1 (MATE1). Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of MATE1, but not BCRP. Acalabrutinib and its active metabolite, ACP-5862, are not inhibitors of P-glycoprotein (P-gp), organic anion transporter (OAT) 1, OAT3, organic cation transporter 2 (OCT2), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or MATE2-K.

Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-gp and BCRP. Acalabrutinib is not a substrate of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Acalabrutinib’s active metabolite, ACP-5862, is not a substrate of OATP1B1 or OATP1B3.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with acalabrutinib.

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.

14 Clinical Studies

14.1 Previously Untreated Mantle Cell Lymphoma Docvariable Vault_Nd_4D1E0C80-2Ff6-409F-Bee7-897264Eadbff \* Mergeformat

ECHO

<div class="scrollingtable"><table width="100%"> <caption> Table 12. Efficacy Results in Patients with Previously Untreated MCL in ECHO </caption> <col width="39%"/> <col width="31%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Outcomes per IRC </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE plus BR N= 299 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Placebo plus BR N= 299 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Progression-Free Survivala </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Median (95% CI), months</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 66.4 (55.1, NE) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 49.6 (36.0, 64.1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>HRb (95% CI)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.73 (0.57, 0.94) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>P-valuec </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.016 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (ORR) (CR + PR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>ORR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 272 (91) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 263 (88) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>95% CI</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 87, 94 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 84, 91 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 199 (67) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 160 (54) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>PR n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 73 (24) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 103 (34) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.220 </td> </tr> <tr class="Last"> <td colspan="3" valign="top"> HR = hazard ratio, CR = complete response, PR = partial response, NE – not evaluable </td> </tr> </tbody> </table></div>

a Stratified by randomization stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]).

b Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI).

c Estimated based on stratified log-rank test for p-value, with an alpha level of 0.039 derived by the O’Brien-Fleming method.

Figure 1. Kaplan-Meier Curve of IRC-Assessed PFS in Patients with Previously Untreated MCL in ECHO

14.2 Previously Treated Mantle Cell Lymphoma

ACE-LY-004

<div class="scrollingtable"><table width="99.92%"> <caption> Table 13: Efficacy Results in Patients with MCL in Trial LY-004 </caption> <col width="42%"/> <col width="26%"/> <col width="31%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Per 2014 Lugano Classification.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Investigator Assessed N=124 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Independent Review Committee (IRC) Assessed N=124 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (ORR)<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ORR (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 81 [73, 87] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 80 [72, 87] </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Complete Response (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 [31, 49] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 [31, 49] </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Partial Response (%) [95% CI] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 41 [32, 50] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 [32, 50] </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Duration of Response (DoR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median DoR in months [range] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NE [1+ to 20+] </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NE [0+ to 20+] </td> </tr> <tr class="Last"> <td colspan="3" valign="top"> CI= Confidence Interval; NE=Not Estimable; + indicates censored observations. </td> </tr> </tbody> </table></div>

The median time to best response was 1.9 months.

Lymphocytosis

Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline assessment ≥ 5 x 109/L) 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.

14.3 Chronic Lymphocytic Leukemia

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.

ELEVATE-TN

Patients were randomized in a 1:1:1 ratio into 3 arms to receive:

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 14. The Kaplan-Meier curves for PFS are shown in Figure 2.

<div class="scrollingtable"><table width="100%"> <caption> Table 14: 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%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Per 2008 International Workshop on CLL (IWCLL) criteria.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Kaplan-Meier estimate.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">§</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">¶</a> </dt> <dd>Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE plus Obinutuzumab N=179 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> CALQUENCE Monotherapy N=179 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Obinutuzumab plus Chlorambucil N=177 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> Progression-Free Survival<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Number of events (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 (8) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 26 (15) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 93 (53) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> PD, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9 (5) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 20 (11) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 82 (46) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> Death events, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11 (6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Median (95% CI), months<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NE </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NE (34, NE) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 22.6 (20, 28) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>HR<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> (95% CI)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.10 (0.06, 0.17) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.20 (0.13, 0.30) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value<a class="Sup" href="#footnote-8" name="footnote-reference-8">§</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> Overall Response Rate<a class="Sup" href="#footnote-5">*</a> (CR + CRi + nPR + PR) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>ORR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 168 (94) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 153 (86) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 139 (79) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>(95% CI)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> (89, 97) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> (80, 90) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> (72, 84) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>p-value<a class="Sup" href="#footnote-9" name="footnote-reference-9">¶</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> < 0.0001 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.0763 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> - </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 23 (13) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 8 (5) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CRi, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>nPR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 (1) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 (1) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 (2) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>PR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 143 (80) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 150 (84) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 128 (72) </td> </tr> <tr class="Last"> <td colspan="4" valign="top"> 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. </td> </tr> </tbody> </table></div>

Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN

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.

ASCEND

Patients were randomized in a 1:1 ratio to receive either:

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 to 8), with 47% having at least 2 prior therapies. The investigator’s choice arm had a median of 2 prior therapies (range: 1 to 10), with 57% having at least 2 prior therapies.

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 15. The Kaplan-Meier curve for PFS is shown in Figure 3. There was no statistically significant difference in overall response rates between the two treatment arms..

<div class="scrollingtable"><table width="100%"> <caption> Table 15: 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 class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">CALQUENCE Monotherapy N=155</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Investigator’s Choice of Idelalisib + Rituximab Product or Bendamustine + Rituximab Product N=155</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Per 2008 IWCLL criteria.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Kaplan-Meier estimate.</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">‡</a> </dt> <dd>Based on a stratified Cox-Proportional-Hazards model.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">§</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">¶</a> </dt> <dd>Through a hierarchical testing procedure, the difference in ORR was not statistically significant, based on a Cochran-Mantel-Haenszel test with adjustment for randomization stratification factors.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Progression-Free Survival<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Number of events, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27 (17) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 68 (44) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Disease progression, n </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 59 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Death, n </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 8 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Median (95% CI), months<a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> NE (NE, NE) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16.5 (14.0, 17.1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>HR (95% CI)<a class="Sup" href="#footnote-12" name="footnote-reference-12">‡</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> 0.31 (0.20, 0.49) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>P-value<a class="Sup" href="#footnote-13" name="footnote-reference-13">§</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> < 0.0001 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Overall Response Rate (CR + CRi + nPR + PR)<a class="Sup" href="#footnote-10">*</a><a class="Sup" href="#footnote-14" name="footnote-reference-14">¶</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>ORR, n (%)<a class="Sup" href="#footnote-14">¶</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 126 (81) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 117 (75) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd> (95% CI) </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> (74, 87) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> (68, 82) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 (1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>CRi, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>nPR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>PR, n (%)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 126 (81) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 115 (74) </td> </tr> <tr class="Last"> <td colspan="3" valign="top"> <dl> <dt> </dt> <dd>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</dd> </dl> </td> </tr> </tbody> </table></div>

Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND

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.

16 How Supplied/Storage And Handling

How Supplied

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<div class="scrollingtable"><table width="100%"> <col width="24%"/> <col width="53%"/> <col width="24%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Pack Size </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Contents </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> NDC Number </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 60-count bottle </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> Bottle containing 60 tablets with a child-resistant closure 100 mg, orange, oval, biconvex tablet, with debossment ‘ACA100’ on one side and plain on the reverse </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0310-3512-60 </td> </tr> </tbody> </table></div>

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Storage

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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].

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17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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Serious and Opportunistic Infections

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Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.1)].

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Hemorrhage

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Inform patients to report signs or symptoms of bleeding. Inform patients that CALQUENCE may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)].

Cytopenias

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Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [see Warnings and Precautions (5.3)].

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Second Primary Malignancies

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Cardiac Arrhythmias

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Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.5)].

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Hepatotoxicity, including Drug Induced Liver Injury:

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Pregnancy Complication

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CALQUENCE may cause fetal harm and dystocia. Advise women to use effective contraception during treatment and for 1 week after the last dose of CALQUENCE [see Use in Specific Populations (8.3)].

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Lactation

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Advise females not to breastfeed during treatment with CALQUENCE and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise females not to breastfeed during treatment with CALQUENCE and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]." }

Dosing Instructions

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Instruct patients to take CALQUENCE orally twice daily, about 12 hours apart. CALQUENCE may be taken with or without food. Advise patients that CALQUENCE tablets should be swallowed whole with a glass of water, without chewing, crushing, dissolving, or cutting [see Dosage and Administration (2.1)].

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Missed Dose

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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 tablets to make up for the dose that they missed [see Dosage and Administration (2.1)].

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Drug Interactions

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Advise patients to inform their healthcare providers of all concomitant medications, including over‑the‑counter medications, vitamins and herbal products [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers of all concomitant medications, including over‑the‑counter medications, vitamins and herbal products [see Drug Interactions (7)]." }

Distributed by:

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AstraZeneca Pharmaceuticals LP

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Wilmington, DE 19850

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{ "type": "p", "children": [], "text": "CALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2025" }

Patient Information

<div class="scrollingtable"><table width="100%"> <col width="98%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> PATIENT INFORMATION CALQUENCE® (KAL-kwens) (acalabrutinib) tablets </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> What is CALQUENCE? CALQUENCE is a prescription medicine used to treat adults with: <dl> <dt>•</dt> <dd>Mantle cell lymphoma (MCL) in combination with bendamustine and rituximab in people who have not had prior treatment for MCL and who cannot receive a type of stem cell transplant that uses their own blood stem cells (autologous hematopoietic stem cell transplantation).</dd> <dt>•</dt> <dd>Mantle cell lymphoma (MCL) who have received at least one prior therapy.</dd> <dt>•</dt> <dd>Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).</dd> </dl> It is not known if CALQUENCE is safe and effective in children. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Before taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you: <dl> <dt>•</dt> <dd>have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.</dd> <dt>•</dt> <dd>have bleeding problems.</dd> <dt>•</dt> <dd>have or had heart rhythm problems.</dd> <dt>•</dt> <dd>have an infection.</dd> <dt>•</dt> <dd>have or had liver problems, including hepatitis B virus (HBV) infection.</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).</dd> <dt>o</dt> <dd>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with CALQUENCE</dd> <dt>o</dt> <dd>Females who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for 1 week after the last dose of CALQUENCE.</dd> <dt>•</dt> <dd>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 2 weeks after your last dose of CALQUENCE.</dd> </dl> Tell your healthcare provider about all the medicines you take, 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. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> How should I take CALQUENCE? <dl> <dt>•</dt> <dd>Take CALQUENCE exactly as your healthcare provider tells you to take it.</dd> <dt>•</dt> <dd>Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.</dd> <dt>•</dt> <dd>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.</dd> <dt>•</dt> <dd>Do not switch (interchange) your CALQUENCE tablets with CALQUENCE capsules.</dd> <dt>•</dt> <dd>Take CALQUENCE 2 times a day (about 12 hours apart).</dd> <dt>•</dt> <dd>Take CALQUENCE with or without food.</dd> <dt>•</dt> <dd>Swallow CALQUENCE tablets whole with a glass of water. Do not chew, crush, dissolve, or cut tablets.</dd> <dt>•</dt> <dd>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.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> What are the possible side effects of CALQUENCE? CALQUENCE can cause serious side effects, including: <dl> <dt>•</dt> <dd> Serious infections have happened in people treated 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.</dd> <dt>•</dt> <dd> Bleeding problems (hemorrhage) have happened in people treated 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:<dl> <dt>∘</dt> <dd>blood in your stools or black stools (looks like tar)</dd> <dt>∘</dt> <dd>pink or brown urine</dd> <dt>∘</dt> <dd>unexpected bleeding, or bleeding that is severe or you cannot control</dd> <dt>∘</dt> <dd>vomit blood or vomit that looks like coffee grounds</dd> <dt>∘</dt> <dd>cough up blood or blood clots</dd> <dt>∘</dt> <dd>dizziness</dd> <dt>∘</dt> <dd>weakness</dd> <dt>∘</dt> <dd>confusion</dd> <dt>∘</dt> <dd>changes in your speech</dd> <dt>∘</dt> <dd>headache that lasts a long time</dd> <dt>∘</dt> <dd>bruising or red or purple skin marks</dd> </dl> </dd> <dt>•</dt> <dd> Decrease in blood cell counts. 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.</dd> <dt>•</dt> <dd> Second primary cancers. 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.</dd> <dt>•</dt> <dd> Heart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, and can be serious or lead to death. Tell your healthcare provider if you have any of the following signs or symptoms:<dl> <dt>∘</dt> <dd>fast or irregular heartbeat</dd> <dt>∘</dt> <dd>dizziness</dd> <dt>∘</dt> <dd>feeling faint</dd> <dt>∘</dt> <dd>chest discomfort</dd> <dt>∘</dt> <dd>shortness of breath</dd> </dl> </dd> <dt>•</dt> <dd> Liver problems. Liver problems have happened in people treated with CALQUENCE, and can be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE</dd> </dl> The most common side effects of CALQUENCE include: <dl> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>upper respiratory tract infection</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>muscle and joint pain</dd> <dt>•</dt> <dd>lower respiratory tract infection</dd> <dt>•</dt> <dd>tiredness</dd> </dl> These are not all of the possible side effects of CALQUENCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088. </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> How should I store CALQUENCE? <dl> <dt>•</dt> <dd>Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).</dd> <dt> </dt> <dd> Keep CALQUENCE and all medicines out of the reach of children. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> General information about the safe and effective use of CALQUENCE. 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. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> What are the ingredients in CALQUENCE? Active ingredient: acalabrutinib Inactive ingredients: Tablet core: low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. Tablet coating: copovidone, ferric oxide yellow, ferric oxide red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water, and titanium dioxide. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 CALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2025 For more information, go to <a href="https://www.calquence.com/">www.CALQUENCE.com</a> or call 1-800-236-9933. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"98%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nPATIENT INFORMATION\n\n\nCALQUENCE® (KAL-kwens)\n\n\n(acalabrutinib)\n\n\ntablets\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nWhat is CALQUENCE?\n\nCALQUENCE is a prescription medicine used to treat adults with:\n<dl>\n<dt>•</dt>\n<dd>Mantle cell lymphoma (MCL) in combination with bendamustine and rituximab in people who have not had prior treatment for MCL and who cannot receive a type of stem cell transplant that uses their own blood stem cells (autologous hematopoietic stem cell transplantation).</dd>\n<dt>•</dt>\n<dd>Mantle cell lymphoma (MCL) who have received at least one prior therapy.</dd>\n<dt>•</dt>\n<dd>Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).</dd>\n</dl>\nIt is not known if CALQUENCE is safe and effective in children.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nBefore taking CALQUENCE, tell your healthcare provider about all of your medical conditions, including if you:\n\n<dl>\n<dt>•</dt>\n<dd>have had recent surgery or plan to have surgery. Your healthcare provider may stop CALQUENCE for any planned medical, surgical, or dental procedure.</dd>\n<dt>•</dt>\n<dd>have bleeding problems.</dd>\n<dt>•</dt>\n<dd>have or had heart rhythm problems.</dd>\n<dt>•</dt>\n<dd>have an infection.</dd>\n<dt>•</dt>\n<dd>have or had liver problems, including hepatitis B virus (HBV) infection.</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. CALQUENCE may harm your unborn baby and problems during childbirth (dystocia).</dd>\n<dt>o</dt>\n<dd>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with CALQUENCE</dd>\n<dt>o</dt>\n<dd>Females who are able to become pregnant should use effective birth control (contraception) during treatment with CALQUENCE and for 1 week after the last dose of CALQUENCE.</dd>\n<dt>•</dt>\n<dd>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 2 weeks after your last dose of CALQUENCE.</dd>\n</dl>\n\nTell your healthcare provider about all the medicines you take, 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.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nHow should I take CALQUENCE?\n\n<dl>\n<dt>•</dt>\n<dd>Take CALQUENCE exactly as your healthcare provider tells you to take it.</dd>\n<dt>•</dt>\n<dd>Do not change your dose or stop taking CALQUENCE unless your healthcare provider tells you to.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking CALQUENCE if you develop certain side effects.</dd>\n<dt>•</dt>\n<dd>Do not switch (interchange) your CALQUENCE tablets with CALQUENCE capsules.</dd>\n<dt>•</dt>\n<dd>Take CALQUENCE 2 times a day (about 12 hours apart).</dd>\n<dt>•</dt>\n<dd>Take CALQUENCE with or without food.</dd>\n<dt>•</dt>\n<dd>Swallow CALQUENCE tablets whole with a glass of water. Do not chew, crush, dissolve, or cut tablets.</dd>\n<dt>•</dt>\n<dd>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.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\">\n\nWhat are the possible side effects of CALQUENCE?\n\n\nCALQUENCE can cause serious side effects, including:\n\n<dl>\n<dt>•</dt>\n<dd>\nSerious infections have happened in people treated 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.</dd>\n<dt>•</dt>\n<dd>\nBleeding problems (hemorrhage) have happened in people treated 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:<dl>\n<dt>∘</dt>\n<dd>blood in your stools or black stools (looks like tar)</dd>\n<dt>∘</dt>\n<dd>pink or brown urine</dd>\n<dt>∘</dt>\n<dd>unexpected bleeding, or bleeding that is severe or you cannot control</dd>\n<dt>∘</dt>\n<dd>vomit blood or vomit that looks like coffee grounds</dd>\n<dt>∘</dt>\n<dd>cough up blood or blood clots</dd>\n<dt>∘</dt>\n<dd>dizziness</dd>\n<dt>∘</dt>\n<dd>weakness</dd>\n<dt>∘</dt>\n<dd>confusion</dd>\n<dt>∘</dt>\n<dd>changes in your speech</dd>\n<dt>∘</dt>\n<dd>headache that lasts a long time</dd>\n<dt>∘</dt>\n<dd>bruising or red or purple skin marks</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\nDecrease in blood cell counts. 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.</dd>\n<dt>•</dt>\n<dd>\nSecond primary cancers. 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.</dd>\n<dt>•</dt>\n<dd>\nHeart rhythm problems (cardiac arrhythmias) have happened in people treated with CALQUENCE, and can be serious or lead to death. Tell your healthcare provider if you have any of the following signs or symptoms:<dl>\n<dt>∘</dt>\n<dd>fast or irregular heartbeat</dd>\n<dt>∘</dt>\n<dd>dizziness</dd>\n<dt>∘</dt>\n<dd>feeling faint</dd>\n<dt>∘</dt>\n<dd>chest discomfort</dd>\n<dt>∘</dt>\n<dd>shortness of breath</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\nLiver problems. Liver problems have happened in people treated with CALQUENCE, and can be severe or life-threatening, or lead to death. Contact your healthcare provider if you experience stomach pain or discomfort, urine of dark color or yellowing of your skin. Your healthcare provider will request tests to monitor your liver function during treatment with CALQUENCE</dd>\n</dl>\n\nThe most common side effects of CALQUENCE include:\n\n<dl>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>upper respiratory tract infection</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>muscle and joint pain</dd>\n<dt>•</dt>\n<dd>lower respiratory tract infection</dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n</dl>\nThese are not all of the possible side effects of CALQUENCE.\nCall your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nHow should I store CALQUENCE?\n\n<dl>\n<dt>•</dt>\n<dd>Store CALQUENCE at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n<dt> </dt>\n<dd>\nKeep CALQUENCE and all medicines out of the reach of children.\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n\nGeneral information about the safe and effective use of CALQUENCE.\n\nMedicines 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.\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nWhat are the ingredients in CALQUENCE?\n\n\nActive ingredient: acalabrutinib\n\nInactive ingredients:\n\n\nTablet core: low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate.\n\nTablet coating: copovidone, ferric oxide yellow, ferric oxide red, hypromellose, medium-chain triglycerides, polyethylene glycol 3350, purified water, and titanium dioxide.\nDistributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850\nCALQUENCE is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2025\nFor more information, go to <a href=\"https://www.calquence.com/\">www.CALQUENCE.com</a> or call 1-800-236-9933.\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 1/2025

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Package/Label Principal Display Panel

NDC 0310-3512-60

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CALQUENCE®

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(acalabrutinib) tablets

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100 mg

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Rx only

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Do not chew, crush, dissolve, or cut tablets

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Manufactured for:

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AstraZeneca Pharmaceuticals LP

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Wilmington, DE 19850

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By: AstraZeneca AB

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SE-151 85 Södertälje Sweden

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Product of Switzerland

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Package/Label Principal Display Panel

NDC 0310-4513-60

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CALQUENCE®

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(acalabrutinib) tablets

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100 mg

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Rx only

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Do not chew, crush, dissolve, or cut

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tablets

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Manufactured for:

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AstraZeneca Pharmaceuticals LP

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Wilmington, DE 19850

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AstraZeneca

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60 tablets

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