CALQUENCE ® (acalabrutinib) capsules, for oral use
Initial U.S. Approval: 2017
Brief Summary of Prescribing Information.
For full Prescribing Information consult official package insert.
INDICATIONS AND USAGE
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 Dosage
CALQUENCE as Monotherapy
For patients with CLL or SLL, the recommended dose of CALQUENCE is 100 mg taken orally approximately every
12 hours until disease progression or unacceptable toxicity.
CALQUENCE in Combination with Obinutuzumab
For patients with previously untreated CLL or SLL, the recommended dose of CALQUENCE is 100 mg taken orally
approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle 1 (each
cycle is 28 days). Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing
information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day.
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.
Recommended Dosage for Hepatic Impairment
Avoid administration of CALQUENCE in patients with severe hepatic impairment.
Dose modifications are not required for patients with mild or moderate hepatic impairment [see Use in Specific
Populations (8.6) and Clinical Pharmacology (12.3) in the full Prescribing Information].
Recommended Dosage for Drug Interactions
Dose Modifications for Use with CYP3A Inhibitors or Inducers
These are described in Table 1 [see Drug Interactions (7) in the full Prescribing Information].
Table 1: Recommended Dose Modifications for Use with CYP3A Inhibitors or Inducers
CYP3A Co-administered Drug Recommended CALQUENCE use
Inhibition
Strong CYP3A inhibitor
Avoid concomitant use.
If these inhibitors will be used short-term (such as anti-infectives for up
to seven days), interrupt CALQUENCE.
Moderate CYP3A
inhibitor
100 mg once daily.
Induction
Strong CYP3A inducer
Avoid concomitant use.
If these inducers cannot be avoided, increase CALQUENCE dose to
200 mg approximately every 12 hours.
Concomitant Use with Gastric Acid Reducing Agents
Proton Pump Inhibitors: Avoid concomitant use [see Drug Interactions (7) in the full Prescribing Information].
H2-Receptor Antagonists: Take CALQUENCE 2 hours before taking a H2-receptor antagonist [see Drug Interactions (7)
in the full Prescribing Information].
Antacids: Separate dosing by at least 2 hours [see Drug Interactions (7) in the full Prescribing Information].
Dose Modifications for Adverse Reactions
Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 2.
Table 2: Recommended Dose Modifications for Adverse Reactions
Event
Grade 3 or greater
non-hematologic
toxicities,
Grade 3
thrombocytopenia
with bleeding,
Grade 4
thrombocytopenia
or
Grade 4
neutropenia lasting
longer than 7 days
Adverse Reaction
Occurrence
First and Second
Third
Fourth
Dose Modification
(Starting dose = 100 mg
approximately every 12 hours)
Interrupt CALQUENCE.
Once toxicity has resolved to Grade 1 or baseline level,
CALQUENCE may be resumed at 100 mg approximately every
12 hours.
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.
Discontinue CALQUENCE.
Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
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%). 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 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.
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.
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 3-7 days pre- and post-surgery depending upon the type of
surgery and the risk of bleeding.
Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%),
developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in
12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose,
or discontinue treatment as warranted [see Dose Modifications for Adverse Reactions (2.4) in the full Prescribing
Information].
Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients
exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in
6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.
Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades
of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac
risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g.,
palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
• Serious and Opportunistic Infections [see Warnings and Precautions (5.1) in the full Prescribing Information]
• Hemorrhage [see Warnings and Precautions (5.2) in the full Prescribing Information]
• Cytopenias [see Warnings and Precautions (5.3) in the full Prescribing Information]
• Second Primary Malignancies [see Warnings and Precautions (5.4) in the full Prescribing Information]
• Atrial Fibrillation and Flutter [see Warnings and Precautions (5.5) in the full Prescribing Information]
Clinical Trials Experience
As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of
a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
in practice.
The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in
1029 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 820 patients in 6 trials,
and CALQUENCE with obinutuzumab in 209 patients in 2 trials. Among these recipients of CALQUENCE, 88% were
exposed for at least 6 months and 79% were exposed for at least one year. In this pooled safety population, adverse
reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia,
headache, diarrhea, and musculoskeletal pain.
Chronic Lymphocytic Leukemia
The safety data described below reflect exposure to CALQUENCE (100 mgapproximately every 12 hours, with or
without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials [see Clinical Studies
(14.2) in the full Prescribing Information].
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) in the full Prescribing Information].
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 upper limit of normal (ULN) and total bilirubin
≤ 1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K
antagonists.
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 5 and 6 presents adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.
Table 5: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN)
Body System
Adverse Reaction*
CALQUENCE
plus Obinutuzumab
N=178
All Grades
(%)
Grade ≥ 3
(%)
CALQUENCE
Monotherapy N=179
All Grades
(%)
Grade ≥ 3
(%)
Obinutuzumab
plus Chlorambucil
N=169
All Grades
(%)
Grade ≥ 3
(%)
Infections
Infection † 69 22 ‡ 65 14 ‡ 46 13 ‡
Upper respiratory tract infection a 39 2.8 35 0 17 1.2
Lower respiratory tract infection b 24 8 18 4.5 7 1.8
Urinary tract infection 15 1.7 15 2.8 5 0.6
Blood and lymphatic system disorders §
Neutropenia c 53 37 23 13 78 50
Anemia d 52 12 53 10 54 14
Thrombocytopenia e 51 12 32 3.4 61 16
Lymphocytosis f 12 11 16 15 0.6 0.6
Nervous system disorders
Headache 40 1.1 39 1.1 12 0
Dizziness 20 0 12 0 7 0
Gastrointestinal disorders
Diarrhea 39 4.5 35 0.6 21 1.8
Nausea 20 0 22 0 31 0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain g 37 2.2 32 1.1 16 2.4
Arthralgia 22 1.1 16 0.6 4.7 1.2
General disorders and administration site conditions
Fatigue h 34 2.2 23 1.1 24 1.2
Skin and subcutaneous tissue disorders
Bruising i 31 0 21 0 5 0
Rash j 26 2.2 25 0.6 9 0.6
Vascular disorders
Hemorrhage k 20 1.7 20 1.7 6 0
* 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
§
Derived from adverse reaction and laboratory data
a
Upper respiratory tract infection, nasopharyngitis and sinusitis
b
Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection
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