acalabrutinib 100 MG Oral Capsule [Calquence]

INDICATIONS AND USAGE CALQUENCE is a kinase inhibitor indicated: • In combination with bendamustine and rituximab for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT). (1.1 ) • For the treatment of adult patients with MCL who have received at least one prior therapy. ( 1.2 ) • For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.3 ) 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).

DOSAGE AND ADMINISTRATION • Recommended dose is 100 mg orally approximately every 12 hours; swallow whole with water and with or without food. ( 2.1 ) • Advise patients not to chew, crush, dissolve, or cut tablets. ( 2.1 ) • Manage toxicities using treatment interruption, dose reduction, or discontinuation. ( 2.3 ) • Avoid CALQUENCE in patients with severe hepatic impairment. ( 8.6 ) 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. 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/m 2 on Days 1 and 2 and rituximab 375 mg/m 2 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. CALQUENCE in Combination with Venetoclax 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, unacceptable toxicity or completion of 14 cycles of treatment. Start CALQUENCE at Cycle 1 (each cycle is 28 days). Start venetoclax at Cycle 3 for total of 12 cycles. Start venetoclax at 20 mg daily for first week of treatment and increase weekly as per dosing schedule for 5-week ramp up (up to 400 mg daily) as described in the venetoclax USPI. Refer to the venetoclax USPI for additional details. 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) ]. Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers CYP3A Co-administered Drug Recommended CALQUENCE use Inhibition Strong CYP3A inhibitor 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. Moderate CYP3A inhibitor Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily. Induction Strong CYP3A inducer Avoid co-administration. If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours. 2.3 Dosage Modifications for Adverse Reactions Recommended dosage modifications are provided in Table 2, 3 and 4. Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab Event Adverse Reaction Occurrence Dosage Modification (Starting dose = 100 mg approximately every 12 hours) Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days First and Second Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours. Third 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. Fourth Discontinue CALQUENCE. Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR Adverse Reaction Severity a Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours) Neutropenia b [see Warnings and Precautions (5.3) ] Absolute neutrophil count less than 0.5 x 10 9 /L for greater than 7 days 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 bendamustine b : Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m 2.d,e Thrombocytopenia f [see Warnings and Precautions (5.3) ] Platelet count 25 to 50 x 10 9 /L with clinically significant bleeding or platelet count less than 25 x 10 9 /L 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/m 2.e Non-hematologic adverse reactions [see Warnings and Precautions (5) ] Grade 3 or higher 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/m 2.e 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 10 9 /L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m 2 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 10 9 /L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding. Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with Venetoclax Adverse Reactiona Adverse Reaction Occurrence Dose Modification Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days First occurrence Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE and/or venetoclax at same dose. Second occurrence Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE at same dose and venetoclax at one lower dose levelc. Subsequent occurrence Withhold CALQUENCE and/or venetoclax until toxicity res

WARNINGS AND PRECAUTIONS • Serious and Opportunistic Infections: Monitor for signs and symptoms of infection and treat promptly. ( 5.1 ) • Hemorrhage: Monitor for bleeding and manage appropriately. ( 5.2 ) • Cytopenias: Monitor complete blood counts regularly. ( 5.3 ) • Second Primary Malignancies: Other malignancies have occurred, including skin cancers and other solid tumors. Advise patients to use sun protection. ( 5.4 ) • Cardiac Arrhythmias: Monitor for symptoms of arrhythmias and manage. ( 5.5 ) • Hepatotoxicity, Including Drug Induced Liver Injury: Monitor hepatic function throughout treatment. ( 5.6 ) 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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%) [see Adverse Reactions (6.1) ] . These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% 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. In an additional cohort of patients receiving CALQUENCE in combination with venetoclax with obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25% receiving AVO compared to 14% in patients receiving AV. Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving AV, most commonly due to COVID-19. The safety and effectiveness of AVO has not been established in patients with previously untreated CLL/SLL [see Clinical Studies (14.3) ]. 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 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% 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 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; 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 (2.3) ] . 5.4 Second Primary Malignancies Second primary malignancies, including skin cancers and other solid tumors, occurred in 16% of 2,055 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 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. 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 2.2% of 2,055 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 0.5% 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.

CONTRAINDICATIONS None. None. ( 4 )

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.