CALQUENCE

2 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 break, open, or chew capsules. ( 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 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/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. 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) ] . 2.3 Dose Modifications for Adverse Reactions Recommended dosage modifications are provided in Table 2 and 3. Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab Event Adverse Reaction Occurrence Dose Modification (Starting dose = 100 mg approximately every 12 hours) Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, 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. Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days 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 2 nd or 3 rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 4 th occurrence. For bendamustineb: 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 3 rd occurrence. For bendamustine f : 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 3 rd 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 Reaction a 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 level c . Subsequent occurrence Withhold CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1 or baseline. b,d Grade 3 or 4 thrombocytopenia and/or bleeding f First occurrence Interrupt CALQUENCE and/or venetoclax. When bleeding resolves and thrombocytopenia is Grade ≤ 1 or baseline without transfusion support for 5 consecutive days, restart CALQUENCE and/or venetoclax at same dose. Second occurrence Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart CALQUENCE at same dose and/or restart venetoclax at one lower dose level. e Subsequent occurrences of severe thrombocytopenia Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level. c,d,e Grade 3 or 4 tumour lysis syndrome (TLS) First and subsequent episodes If a subject experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax and acalabrutinib dose should be withheld. If resolved within 24–48 hours of last dose, treatment can be resumed at the same dose. For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at one lower dose level. c When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis. Grade 3 other non-hematologic events g First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1. Restart CALQUENCE and/or venetoclax at same dose. Second occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1 d . Grade 4 other non-hematologic events g First occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level. c, e Second occurrence Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1 d . a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Growth factor may be used at physician discretion. c See venetoclax USPI for dose level reductions details. d Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax. e CALQUENCE dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥ 4 weeks. f Platelets may be used at physician discretion. g Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤ 1 according to the NCI CTCAE definitions. In such cases, if a subject is clinically stable, resumption of CALQUENCE may be possible based on clinical judgement of the treating physician. Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.

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1 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).