6 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)]
•: Hemorrhage [see Warnings and Precautions (5.2)]
•: Cytopenias [see Warnings and Precautions (5.3)]
•: Second Primary Malignancies [see Warnings and Precautions (5.4)]
•: Cardiac Arrhythmias [see Warnings and Precautions (5.5)]
•: Hepatotoxicity, including DILI [see Warnings and Precautions (5.6)]

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.

Table 4: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO
Body System Adverse Reactions*	CALQUENCE plus BR N = 297		Placebo plus BR N = 297
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Skin and subcutaneous tissue disorders
Rasha	47	12	31	3
Infections
COVID-19b	38	13	27	11
Upper respiratory tract infectionc	30	0.7	29	1
Pneumoniad	31	17	25	14
Gastrointestinal disorders
Diarrhea	37	3	28	2.4
Vomiting	26	0.7	14	1
Constipation	25	1	25	0.3
General disorders
Fatigue	37	3.7	32	4.4
Pyrexia	29	2.4	24	1.3
Edema	20	1.3	19	0
Nervous system disorders
Headache	31	1.7	14	0.7
Dizziness	18	1	17	0.3
Respiratory, thoracic and mediastinal disorders
Cough	27	0	20	0.3
Dyspnea	17	1	11	2.7
Neoplasms
Secondary primary malignancye	19	7	15	7
Musculoskeletal and connective tissue disorders
Arthralgia	18	0.7	16	1
Vascular disorders
Hemorrhagef	20	1.7	11	3
*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.

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

Table 5: Select Laboratory Abnormalities (≥ 15%) in Patients with Previously Untreated MCL in ECHO
Laboratory Abnormality	CALQUENCE plus BR		Placebo plus BR
Laboratory Abnormality	All grade (%)	Grade 3 or 4 (%)	All grade (%)	Grade 3 or 4 (%)
Hematologic Abnormalities
Lymphocytes decreased	98	87	97	89
Hemoglobin decreased	80	11	65	11
Neutrophils decreased	76	56	77	51
Platelets decreased	69	18	60	16
Chemistry Abnormalities
AST increased	53	5	50	3.4
Uric acid increased	45	45	40	40
ALT increased	44	7	41	2.4
Potassium increased	40	2	38	2.7
Creatinine increased	37	3	28	2.4
Phosphate decreased	36	4.4	30	4.7
Potassium decreased	29	7	23	6
Bilirubin increased	19	2	12	2
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.

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.

Table 6: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004
Body System Adverse Reactions*	CALQUENCE Monotherapy N=124
Body System Adverse Reactions*	All Grades (%)	Grade ≥ 3 (%)
Nervous system disorders
Headache	39	1.6
Gastrointestinal disorders
Diarrhea	31	3.2
Nausea	19	0.8
Abdominal pain	15	1.6
Constipation	15	-
Vomiting	13	1.6
General disorders
Fatigue	28	0.8
Musculoskeletal and connective tissue disorders
Myalgia	21	0.8
Skin and subcutaneous tissue disorders
Bruisinga	21	-
Rashb	18	0.8
Vascular disorders
Hemorrhagec	8	0.8
Respiratory, thoracic and mediastinal disorders
Epistaxis	6	-

*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’.

Table 7: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY 004
Hematologic Adverse Reactions*	CALQUENCE Monotherapy N=124
Hematologic Adverse Reactions*	All Grades (%)	Grade ≥ 3 (%)
Hemoglobin decreased	46	10
Platelets decreased	44	12
Neutrophils decreased	36	15

*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 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 (14.3)].

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.

Table 8: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN)
Body System Adverse Reaction*	CALQUENCE plus Obinutuzumab N=178		CALQUENCE Monotherapy N=179		Obinutuzumab plus Chlorambucil N=169
Body System Adverse Reaction*	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
Infections
Infection†	69	22‡	65	14‡	46	13‡
Upper respiratory tract infection§	39	2.8	35	0	17	1.2
Lower respiratory tract infectiona	24	8	18	4.5	7	1.8
Urinary tract infection	15	1.7	15	2.8	5	0.6
Blood and lymphatic system disordersb
Neutropeniac	53	37	23	13	78	50
Anemiad	52	12	53	10	54	14
Thrombocytopeniae	51	12	32	3.4	61	16
Lymphocytosisf	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 paing	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
Fatigueh	34	2.2	23	1.1	24	1.2
Skin and subcutaneous tissue disorders
Bruisingi	31	0	21	0	5	0
Rashj	26	2.2	25	0.6	9	0.6
Vascular disorders
Hemorrhagek	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.

§ 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:

•: Neoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%)
•: Cardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%)
•: Infection: herpesvirus infection (6%)

Table 9: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)
Laboratory Abnormality*†	CALQUENCE plus Obinutuzumab N=178		CALQUENCE Monotherapy N=179		Obinutuzumab plus Chlorambucil N=169
Laboratory Abnormality*†	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
* Per NCI CTCAE version 4.03 † Excludes electrolytes
Uric acid increase	29	29	22	22	37	37
ALT increase	30	7	20	1.1	36	6
AST increase	38	5	17	0.6	60	8
Bilirubin increase	13	0.6	15	0.6	11	0.6

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.

Table 10: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND)
Body System Adverse Reaction*	CALQUENCE N=154		Idelalisib plus Rituximab Product N=118		Bendamustine plus Rituximab Product N=35
Body System Adverse Reaction*	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
Infections
Infection†	56	15‡	65	28‡	49	11
Upper respiratory tract infection§	29	1.9	26	3.4	17	2.9
Lower respiratory tract infection a	23	6	26	15	14	6
Blood and lymphatic system disordersb
Neutropeniac	48	23	79	53	80	40
Anemiad	47	15	45	8	57	17
Thrombocytopeniae	33	6	41	13	54	6
Lymphocytosisf	26	19	23	18	2.9	2.9
Nervous system disorders
Headache	22	0.6	6	0	0	0
Gastrointestinal disorders
Diarrheag	18	1.3	49	25	14	0
Vascular disorders
Hemorrhageh	16	1.3	5	1.7	6	2.9
General disorders
Fatiguei	15	1.9	13	0.8	31	6
Musculoskeletal and connective tissue disorders
Musculoskeletal painj	15	1.3	15	1.7	2.9	0

* 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:

•: Skin and subcutaneous disorders: bruising (10%), rash (9%)
•: Neoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%)
•: Musculoskeletal and connective tissue disorders: arthralgia (8%)
•: Cardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%)
•: Infection: herpesvirus infection (4.5%)

Table 11: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)
Laboratory Abnormality*	CALQUENCE N=154		Idelalisib plus Rituximab Product N=118		Bendamustine plus Rituximab Product N=35
Laboratory Abnormality*	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
* Excludes electrolytes
Uric acid increase	15	15	11	11	23	23
ALT increase	15	1.9	59	23	26	2.9
AST increase	13	0.6	48	13	31	2.9
Bilirubin increase	13	1.3	16	1.7	26	11
Per NCI CTCAE version 5

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.

•: Cardiac disorders: ventricular arrhythmias
•: Hepatobiliary disorder: Drug induced liver injury