6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Tumor Lysis Syndrome [see Warnings and Precautions (5.1)]
Neutropenia [see Warnings and Precautions (5.2)]
Infections [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

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

In CLL/SLL, the safety population reflects exposure to VENCLEXTA as monotherapy in patients in M13-982, M14-032, and M12-175 and in combination with obinutuzumab or rituximab in patients in CLL14 and MURANO. In this CLL/SLL safety population, the most common adverse reactions (≥20%) for VENCLEXTA were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

In AML, the safety population reflects exposure to VENCLEXTA in combination with decitabine, azacitidine, or low-dose cytarabine in patients in M14-358, VIALE-A, and VIALE-C. In this safety population, the most common adverse reactions (≥30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

VENCLEXTA in Combination with Obinutuzumab

The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) (N=212) versus obinutuzumab in combination with chlorambucil (GClb) (N=214) was evaluated in CLL14, a randomized, open-label, actively controlled trial in patients with previously untreated CLL [see Clinical Studies (14.1)]. Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles. Patients initiated the first dose of the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once completed, continued VENCLEXTA 400 mg orally once daily for a total of 12 cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. The median duration of exposure to VENCLEXTA was 10.5 months (range: 0 to 13.5 months) and the median number of cycles of obinutuzumab was 6 in the VEN+G arm.

Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.

In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. Neutropenia led to discontinuation of VENCLEXTA in 2% of patients, dose reduction in 13%, and dose interruption in 41%.

Table 9 presents adverse reactions identified in CLL14.

Table 9. Adverse Reactions (≥10%) in Patients Treated with VEN+G in CLL14
Adverse Reaction	VENCLEXTA + Obinutuzumab (N = 212)		Obinutuzumab + Chlorambucil (N = 214)
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Blood and lymphatic system disorders
Neutropeniaa	60	56	62	52
Anemiaa	17	8	20	7
Gastrointestinal disorders
Diarrhea	28	4	15	1
Nausea	19	0	22	1
Constipation	13	0	9	0
Vomiting	10	1	8	1
General disorders and administration site conditions
Fatiguea	21	2	23	1
Infections and infestations
Upper respiratory tract infectiona	17	1	17	1
aIncludes multiple adverse reaction terms.

Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+G are presented below:

Blood and lymphatic system disorders: febrile neutropenia (6%)

Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%)

Metabolism and nutrition disorder: tumor lysis syndrome (1%)

During treatment with VENCLEXTA monotherapy after completion of VEN+G, the adverse reaction that occurred in ≥10% of patients was neutropenia (26%). The grade ≥3 adverse reactions that occurred in ≥2% of patients were neutropenia (23%) and anemia (2%).

Table 10 presents laboratory abnormalities CLL14.

Table 10. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+G in CLL14
Laboratory Abnormalitya	VENCLEXTA + Obinutuzumab (N = 212)		Obinutuzumab + Chlorambucil (N = 214)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Leukopenia	90	46	89	41
Lymphopenia	87	57	87	51
Neutropenia	83	63	79	56
Thrombocytopenia	68	28	71	26
Anemia	53	15	46	11
Chemistry
Blood creatinine increased	80	6	74	2
Hypocalcemia	67	9	58	4
Hyperkalemia	41	4	35	3
Hyperuricemia	38	38	38	38
aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown.

Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+G included neutropenia (32%), leukopenia and lymphopenia (10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia (2%).

VENCLEXTA in Combination with Rituximab

The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) versus bendamustine in combination with rituximab (B+R) (N=188) was evaluated in MURANO [see Clinical Studies (14.1)]. Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily, in combination with rituximab for 6 cycles followed by VENCLEXTA monotherapy, for a total of 24 months after ramp-up. At the time of analysis, the median duration of exposure to VENCLEXTA was 22 months and the median number of cycles of rituximab was 6 in the VEN+R arm.

Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients.

In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Neutropenia and thrombocytopenia each led to discontinuation of VENCLEXTA in 3% of patients. Neutropenia led to dose interruption of VENCLEXTA in 46% of patients.

Table 11 presents adverse reactions identified in MURANO.

Table 11. Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO
Adverse Reaction	VENCLEXTA + Rituximab (N = 194)		Bendamustine + Rituximab (N = 188)
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Blood and lymphatic system disorders
Neutropeniaa	65	62	50	44
Anemiaa	16	11	23	14
Gastrointestinal disorders
Diarrhea	40	3	17	1
Nausea	21	1	34	1
Constipation	14	<1	21	0
Infections and infestations
Upper respiratory tract infectiona	39	2	23	2
Lower respiratory tract infectiona	18	2	10	2
Pneumoniaa	10	7	14	10
General disorders and administration site conditions
Fatiguea	22	2	26	<1
aIncludes multiple adverse reaction terms.

Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+R are presented below:

Blood and lymphatic system disorders: febrile neutropenia (4%)

Gastrointestinal disorders: vomiting (8%)

Infections and infestations: sepsis (<1%)

Metabolism and nutrition disorders: tumor lysis syndrome (3%)

During treatment with VENCLEXTA monotherapy after completion of VEN+R combination treatment, adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in ≥2% of patients were neutropenia (12%) and anemia (3%).

Table 12 presents laboratory abnormalities identified in MURANO.

Table 12. New or Worsening Clinically Important Laboratory Abnormalities (≥10%) in Patients Treated with VEN+R in MURANO
Laboratory Abnormality	VENCLEXTA + Rituximab (N = 194)		Bendamustine + Rituximab (N = 188)
	All Gradesa (%)	Grade 3 or 4 (%)	All Gradesa (%)	Grade 3 or 4 (%)
Hematology
Leukopenia	89	46	81	35
Lymphopenia	87	56	79	55
Neutropenia	86	64	84	59
Anemia	50	12	63	15
Thrombocytopenia	49	15	60	20
Chemistry
Blood creatinine increased	77	<1	78	1
Hypocalcemia	62	5	51	2
Hyperuricemia	36	36	33	33
Hyperkalemia	24	3	19	2
aIncludes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown.

Grade 4 laboratory abnormalities that developed in ≥2% of patients treated with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%).

VENCLEXTA as Monotherapy

The safety of VENCLEXTA was evaluated in pooled data from three single-arm trials (M13-982, M14-032, and M12-175). Patients received VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks.

In the pooled dataset, the median age was 66 years (range: 28 to 85 years), 93% were White, and 68% were male. The median number of prior therapies was 3 (range: 0 to 15).

Serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock.

Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia. The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%).

Table 13 presents adverse reactions identified in these trials.

Table 13. Adverse Reactions Reported in ≥10% (All Grades) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy
Adverse Reaction	VENCLEXTA (N = 352)
	All Grades (%)	Grade ≥3 (%)
Blood and lymphatic system disorders
Neutropeniaa	50	45
Anemiaa	33	18
Thrombocytopeniaa	29	20
Lymphopeniaa	11	7
Febrile neutropenia	6	6
Gastrointestinal disorders
Diarrhea	43	3
Nausea	42	1
Abdominal paina	18	3
Vomiting	16	1
Constipation	16	<1
Mucositisa	13	<1
Infections and infestations
Upper respiratory tract infectiona	36	1
Pneumoniaa	14	8
Lower respiratory tract infectiona	11	2
General disorders and administration site conditions
Fatiguea	32	4
Edemaa	22	2
Pyrexia	18	<1
Musculoskeletal and connective tissue disorders
Musculoskeletal paina	29	2
Arthralgia	12	<1
Respiratory, thoracic, and mediastinal disorders
Cougha	22	0
Dyspneaa	13	1
Nervous system disorders
Headache	18	<1
Dizzinessa	14	0
Skin and subcutaneous tissue disorders
Rasha	18	<1
Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms.

Table 14 presents laboratory abnormalities reported throughout treatment that were new or worsening from baseline. The most common (>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities, including neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%).

Table 14. New or Worsening Laboratory Abnormalities in ≥40% (All Grades) or ≥10% (Grade 3 or 4) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy
Laboratory Abnormality	VENCLEXTA (N = 352)
	All Gradesa (%)	Grade 3 or 4 (%)
Hematology
Leukopenia	89	42
Neutropenia	87	63
Lymphopenia	74	40
Anemia	71	26
Thrombocytopenia	64	31
Chemistry
Hypocalcemia	87	12
Hyperglycemia	67	7
Hyperkalemia	59	5
AST increased	53	3
Hypoalbuminemia	49	2
Hypophosphatemia	45	11
Hyponatremia	40	9
aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown.

Important Adverse Reactions in CLL/SLL

Tumor Lysis Syndrome

Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA.

CLL14

The incidence of TLS was 1% (3/212) in patients treated with VEN+G [see Warnings and Precautions (5.1)]. All three events of TLS resolved and did not lead to withdrawal from the trial. Obinutuzumab administration was delayed in two cases in response to the TLS events.

MURANO

The incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the trial, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in sections 2.2 and 2.4 [see Dosage and Administration (2.2, 2.4)]. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days. All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures [see Dosage and Administration (2.2, 2.4)]. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 12.

Monotherapy Studies (M13-982 and M14-032)

In 168 patients with CLL treated according to recommendations described in sections 2.1 and 2.2, the rate of TLS was 2% [see Dosage and Administration (2.2, 2.4)]. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L), or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm and/or absolute lymphocyte count (ALC) ≥25 x 109/L. All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and hyperuricemia (10% all Grades, <1% Grade ≥3).

In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis. After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised [see Dosage and Administration (2.2, 2.4)].

Acute Myeloid Leukemia

VENCLEXTA in Combination with Azacitidine

The safety of VENCLEXTA in combination with azacitidine (VEN+AZA) (N=283) versus placebo in combination with azacitidine (PBO+AZA) (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, in patients with newly diagnosed AML [see Clinical Studies (14.2)]. At baseline, patients were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients were randomized to receive VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or placebo in combination with azacitidine. Among patients who received VEN+AZA, the median duration of exposure to VENCLEXTA was 7.6 months (range: <0.1 to 30.7 months).

Serious adverse reactions were reported in 83% of patients who received VEN+AZA, with the most frequent (≥5%) being febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). Fatal adverse reactions occurred in 23% of patients who received VEN+AZA, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).

Adverse reactions led to permanent discontinuation of VENCLEXTA in 24% of patients, dose reductions in 2%, and dose interruptions in 72%. Adverse reactions which led to discontinuation of VENCLEXTA in ≥2% of patients were sepsis (excluding fungal; 3%) and pneumonia (2%). The most frequent adverse reaction leading to dose reduction was pneumonia (0.7%). Adverse reactions which required a dose interruption in ≥5% of patients included febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopenia (10%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) <500/microliter.

Table 15 presents adverse reactions identified in VIALE-A.

Table 15. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A
Adverse Reaction	VENCLEXTA + Azacitidine (N = 283)		Placebo + Azacitidine (N = 144)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders
Nausea	44	2	35	<1
Diarrheaa	43	5	33	3
Vomitingb	30	2	23	<1
Stomatitisc	18	1	13	0
Abdominal paind	18	<1	13	0
Blood and lymphatic system disorders
Febrile neutropenia	42	42	19	19
Musculoskeletal and connective tissue disorders
Musculoskeletal paine	36	2	28	1
General disorders and administration site conditions
Fatiguef	31	6	23	2
Edemag	27	<1	19	0
Vascular disorders
Hemorrhageh	27	7	24	3
Hypotensioni	12	5	8	3
Metabolism and nutrition disorders
Decreased appetitej	25	4	17	<1
Skin and subcutaneous tissue disorders
Rashk	25	1	15	0
Infections and infestations
Sepsisl (excluding fungal)	22	22	16	14
Urinary tract infectionm	16	6	9	6
Respiratory, thoracic and mediastinal disorders
Dyspnean	18	4	10	2
Nervous system disorders
Dizzinesso	17	<1	8	<1
aIncludes diarrhea and colitis. bIncludes vomiting and hematemesis. cIncludes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, aphthous ulcer, glossitis, and tongue ulceration. dIncludes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. eIncludes arthralgia, back pain, pain in extremity, musculoskeletal pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and musculoskeletal discomfort. fIncludes fatigue and asthenia. gIncludes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling. hIncludes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, hemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, hemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, gastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, upper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, gastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, lower gastrointestinal hemorrhage, mucosal hemorrhage, penile hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture site hemorrhage, vitreous hemorrhage, and wound hemorrhage. iIncludes hypotension and orthostatic hypotension. jIncludes decreased appetite and hypophagia. kIncludes rash, rash maculo-papular, rash macular, drug eruption, rash papular, rash pustular, eczema, rash erythematous, rash pruritic, dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, exfoliative rash, and perivascular dermatitis. lIncludes sepsis, escherichia bacteremia, escherichia sepsis, septic shock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, staphylococcal sepsis, streptococcal bacteremia, enterococcal bacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal sepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal sepsis, neutropenic sepsis, and streptococcal sepsis. mIncludes urinary tract infection, escherichia urinary tract infection, cystitis, urinary tract infection enterococcal, urinary tract infection bacterial, pyelonephritis acute, and urinary tract infection pseudomonal. nIncludes dyspnea, dyspnea exertional, and dyspnea at rest. oIncludes dizziness and vertigo.

Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 15 or <10% are presented below:

Hepatobiliary disorders: cholecystitis/cholelithiasisa (4%)

Infections and infestations: pneumoniab (33%)

Metabolism and nutrition disorders: tumor lysis syndrome (1%)

Nervous system disorders: headachec (11%)

Investigations: weight decreased (13%).

aIncludes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic.
bIncludes pneumonia, lung infection, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia viral, lower respiratory tract infection fungal, pneumonia hemophilus, pneumonia pneumococcal, and pneumonia respiratory syncytial viral.
cIncludes headache and tension headache.

Table 16 presents laboratory abnormalities identified in VIALE-A.

Table 16. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+AZA with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+AZA in VIALE-A
Laboratory Abnormality	VENCLEXTA + Azacitidine		Placebo + Azacitidine
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Neutrophils decreased	98	98	88	81
Platelet decreased	94	88	94	80
Lymphocytes decreased	91	71	72	39
Hemoglobin decreased	61	57	56	52
Chemistry
Bilirubin increased	53	7	40	4
Calcium decreased	51	6	39	9
Sodium decreased	46	14	47	8
Alkaline phosphatase increased	42	1	29	<1
Blood bicarbonate decreased	31	<1	25	0
The denominator used to calculate the rate varied from 85 to 144 in the PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on the number of patients with at least one post-treatment value.

VENCLEXTA in Combination with Azacitidine or Decitabine

The safety of VENCLEXTA in combination with azacitidine (N=67) or decitabine (N=13) was evaluated in M14-358, a non-randomized trial of patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity [see Clinical Studies (14.2)]. Patients received VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or decitabine (20 mg/m2 intravenously on Days 1-5 of each 28-day cycle).

Azacitidine

The median duration of exposure to VENCLEXTA when administered in combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months). The safety of VENCLEXTA in combination with azacitidine in this trial is consistent with that of VIALE-A.

Decitabine

The median duration of exposure to VENCLEXTA when administered in combination with decitabine was 8.4 months (range: 0.5 to 39 months).

Serious adverse reactions were reported in 85% of patients who received VENCLEXTA with decitabine, the most frequent (≥10%) being sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment.

Permanent discontinuation of VENCLEXTA due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to permanent discontinuation (≥5%) was pneumonia (8%).

Dosage reductions of VENCLEXTA due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia (15%).

Dosage interruptions of VENCLEXTA due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions leading to dose interruption (≥10%) were neutropenia (38%), febrile neutropenia (23%), leukopenia (15%), and pneumonia (15%).

The most common adverse reactions (≥30%) were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). The most common laboratory abnormalities (≥30%) were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), calcium decreased (85%), hemoglobin decreased (69%), glucose increased (69%), magnesium decreased (54%), potassium decreased (46%), bilirubin increased (46%), albumin decreased (38%), alkaline phosphatase increased (38%), sodium decreased (38%), ALT increased (31%), creatinine increased (31%), and potassium increased (31%).

VENCLEXTA in Combination with Low-Dose Cytarabine

VIALE-C

The safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomized trial in patients with newly diagnosed AML. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity [see Clinical Studies (14.2)]. Patients were randomized to receive VENCLEXTA 600 mg orally once daily after completion of a 4-day ramp-up phase in combination with low-dose cytarabine (20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle) or placebo in combination with low-dose cytarabine. Among patients who received VEN+LDAC, the median duration of exposure to VENCLEXTA was 3.9 months (range: <0.1 to 17.1 months).

Serious adverse reactions were reported in 65% of patients who received VEN+LDAC, with the most frequent (≥10%) being pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverse reactions occurred in 23% of patients who received VEN+LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).

Adverse reactions led to permanent discontinuation of VENCLEXTA in 25% of patients, dose reductions in 9%, and dose interruptions in 63%. The most frequent adverse reaction (>2%) which resulted in permanent discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions which required a dose reduction in ≥1% of patients were pneumonia (1%) and thrombocytopenia (1%), and the adverse reactions which required a dose interruption in ≥5% of patients included neutropenia (20%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and sepsis (excluding fungal; 6%). Among patients who achieved bone marrow clearance of leukemia, 32% underwent dose interruptions for ANC <500/microliter.

Table 17 presents adverse reactions identified in VIALE-C.

Table 17. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+LDAC with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-C
Adverse Reaction	VENCLEXTA + Low-Dose Cytarabine (N = 142)		Placebo + Low-Dose Cytarabine (N = 68)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders
Nausea	42	1	31	0
Diarrhea	28	3	16	0
Vomiting	25	<1	13	0
Abdominal paina	15	<1	9	3
Stomatitisb	15	1	6	0
Blood and lymphatic system disorders
Febrile neutropenia	32	32	29	29
Infections and infestations
Pneumoniac	29	19	21	21
Vascular Disorders
Hemorrhaged	27	8	16	1
Hypotensione	11	5	4	1
Musculoskeletal and connective tissue disorders
Musculoskeletal painf	23	3	18	0
General Disorders and Administration Site Conditions
Fatigueg	22	2	21	0
Nervous System Disorders
Headache	11	0	6	0
aIncludes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. bIncludes stomatitis, mouth ulceration, aphthous ulcer, glossitis, mucosal inflammation, and tongue ulceration. cIncludes pneumonia, lung infection, lower respiratory tract infection, pneumonia fungal, lower respiratory tract infection fungal, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, and pneumonia pseudomonal. dIncludes epistaxis, conjunctival hemorrhage, hemoptysis, gastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage, upper gastrointestinal hemorrhage, hematuria, retinal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage, gastritis hemorrhagic, hemorrhage intracranial, hemorrhage subcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary alveolar hemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterine hemorrhage, and vascular access site hemorrhage. eIncludes hypotension and orthostatic hypotension. fIncludes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain, musculoskeletal chest pain, and spinal pain. gIncludes fatigue and asthenia.

Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 17 or <10% are presented below:

Hepatobiliary disorders: cholecystitis/cholelithiasisa (1%)

Infections and infestations: sepsisb (excluding fungal; 15%), urinary tract infectionc (8%)

Metabolism and nutrition disorders: decreased appetite (19%), tumor lysis syndrome (6%)

Nervous system disorders: dizzinessd (9%)

Respiratory, thoracic, and mediastinal disorders: dyspneae (10%)

Investigations: weight decreased (9%).

aIncludes cholecystitis and cholecystitis acute.
bIncludes sepsis, bacteremia, septic shock, neutropenic sepsis, staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis, Escherichia bacteremia, pseudomonal bacteremia, and staphylococcal sepsis.
cIncludes urinary tract infection and escherichia urinary tract infection.
dIncludes dizziness and vertigo.
eIncludes dyspnea and dyspnea exertional.

Table 18 describes laboratory abnormalities identified in VIALE-C.

Table 18. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+LDAC with Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+LDAC in VIALE-C
Laboratory Abnormality	VENCLEXTA + Low-Dose Cytarabine		Placebo + Low-Dose Cytarabine
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Platelets decreased	97	95	92	90
Neutrophils decreased	95	92	82	71
Lymphocytes decreased	92	69	65	24
Hemoglobin decreased	63	57	57	54
Chemistry
Bilirubin increased	61	7	38	7
Albumin decreased	61	6	43	4
Potassium decreased	56	16	42	14
Calcium decreased	53	8	45	13
Glucose increased	52	13	59	9
AST increased	36	6	37	1
Alkaline phosphatase increased	34	1	26	1
ALT increased	30	4	26	1
Sodium increased	11	3	6	1
The denominator used to calculate the rate varied from 38 to 68 in the PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on the number of patients with at least one post-treatment value.

M14-387

The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open- label trial of patients with newly diagnosed AML [see Clinical Studies (14.2)]. At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. Patients received VENCLEXTA 600 mg orally once daily after completion of the ramp-up phase in combination with low-dose cytarabine (20mg/m2 subcutaneously on Days 1-10 of each 28-day cycle). The safety of VENCLEXTA in combination with low-dose cytarabine is consistent with that of VIALE-C.