VENCLEXTA SIDE EFFECTS
- Generic Name: venetoclax tablets
- Brand Name: Venclexta
- Drug Class: B-Cell Lymphoma Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Tumor Lysis Syndrome
- Neutropenia
- Infections
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. 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 dose interruption of VENCLEXTA in 41% of patients, reduction in 13%, and discontinuation in 2%.
Table 1 presents adverse reactions identified in CLL14.
Table 1: 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 2 presents laboratory abnormalities CLL14.
Table 2: 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 |
| Thrombocytopeni a | 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. 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 single agent VENCLEXTA 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 led to dose interruption of VENCLEXTA in 46% of patients and discontinuation in 3% and thrombocytopenia led to discontinuation in 3% of patients.
Table 3: Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO Table 11 presents adverse reactions identified 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 4 presents laboratory abnormalities identified in MURANO.
Table 4: 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 |
| Thrombocytopeni a | 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 (M13982, 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 5 presents adverse reactions identified in these trials.
Table 5: 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 6 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 6: 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. 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. 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. 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%. 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 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.
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.. 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 VENCLEXTA in combination with azacitidine, 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 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 7 presents laboratory abnormalities identified in VIALE-A.
Table 7: 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 PBO+AZA and from 125 to 283 in VEN+AZA 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. 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 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%).
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%).
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. 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 VENCLEXTA in combination with 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 8 presents adverse reactions identified in VIALE-C.
Table 8: 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 the 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 9 describes laboratory abnormalities identified in VIALE-C.
Table 9: 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 PBO+LDAC and from 65 to 142 in VEN+LDAC 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. 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.
SRC: NLM .