Venclexta

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 10/14/2021
Venclexta Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Venclexta?

Venclexta (venetoclax) is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

What Are Side Effects of Venclexta?

Common side effects of Venclexta include:

Dosage for Venclexta

The starting dose of Venclexta is 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg.

What Drugs, Substances, or Supplements Interact with Venclexta?

Venclexta may interact with azole antifungals, conivaptan, clarithromycin, protease inhibitors, erythromycin, ciprofloxacin, diltiazem, dronedarone, verapamil, amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor, rifampin, carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin, warfarin, digoxin, everolimus, sirolimus, grapefruit products, Seville oranges, and starfruit. Tell your doctor all medications and supplements you use. During pregnancy, Venclexta should only be taken if prescribed.

Venclexta During Pregnancy and Breastfeeding

Tell your doctor if you become pregnant while taking Venclexta; it may harm a fetus. It is unknown if Venclexta passes into breast milk. Breastfeeding while taking Venclexta is not recommended.

Additional Information

Our Venclexta (venetoclax) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Venclexta Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • symptoms of sepsis--confusion, severe drowsiness, rapid breathing, feeling very ill;
  • signs of pneumonia--cough with yellow or green mucus, stabbing chest pain, wheezing, trouble breathing;
  • low blood cell counts--fever, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed; or
  • signs of tumor cell breakdown--chills, joint or muscle pain, feeling tired or short of breath, fast or slow heartbeats, nausea, vomiting, dark or cloudy urine, or seizure (convulsions).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

  • stomach pain, nausea, vomiting, diarrhea, constipation;
  • feeling tired or short of breath;
  • low blood pressure, feeling dizzy or lightheaded;
  • muscle and joint pain;
  • swelling in your arms, legs, hands, and feet;
  • fever, low blood cell counts;
  • pneumonia, sepsis;
  • mouth pain;
  • rash; or
  • cold symptoms such as stuffy nose, sneezing, sore throat, cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Venclexta (Venetoclax Tablets)

QUESTION

What is leukemia? See Answer
Venclexta Professional Information

SIDE EFFECTS

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

  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Neutropenia [see WARNINGS AND PRECAUTIONS]
  • Infections [see WARNINGS AND PRECAUTIONS]

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]. 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 9 presents adverse reactions identified in CLL14.

Table 9: Adverse Reactions (≥10%) in Patients Treated with VEN+G in CLL14

Adverse ReactionVENCLEXTA + Obinutuzumab
(N = 212)
Obinutuzumab + Chlorambucil
(N = 214)
All Grades (%)Grade ≥ 3 (%)All Grades (%)Grade ≥ 3 (%)
Blood and lymphatic system disorders
Neutropeniaa60566252
Anemiaa178207
Gastrointestinal disorders
Diarrhea284151
Nausea190221
Constipation13090
Vomiting10181
General disorders and administration site conditions
Fatiguea212231
Infections and infestations
Upper respiratory tract infectiona171171
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 AbnormalityaVENCLEXTA + Obinutuzumab
(N = 212)
Obinutuzumab + Chlorambucil
(N = 214)
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Hematology
Leukopenia90468941
Lymphopenia87578751
Neutropenia83637956
Thrombocytopeni a68287126
Anemia53154611
Chemistry
Blood creatinine increased806742
Hypocalcemia679584
Hyperkalemia414353
Hyperuricemia38383838
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]. 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 11: Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO Table 11 presents adverse reactions identified in MURANO.

Adverse ReactionVENCLEXTA + Rituximab
(N = 194)
Bendamustine + Rituximab
(N = 188)
All Grades (%)Grade ≥ 3 (%)All Grades (%)Grade ≥ 3 (%)
Blood and lymphatic system disorders
Neutropeniaa65625044
Anemiaa16112314
Gastrointestinal disorders
Diarrhea403171
Nausea211341
Constipation14<1210
Infections and infestations
Upper respiratory tract infectiona392232
Lower respiratory tract infectiona182102
Pneumoniaa1071410
General disorders and administration site conditions
Fatiguea22226<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 AbnormalityVENCLEXTA + Rituximab
(N = 194)
Bendamustine + Rituximab
(N = 188)
All Gradesa (%)Grade 3 or 4 (%)All Gradesa (%)Grade 3 or 4 (%)
Hematology
Leukopenia89468135
Lymphopenia87567955
Neutropenia86648459
Anemia50126315
Thrombocytopeni a49156020
Chemistry
Blood creatinine increased77<1781
Hypocalcemia625512
Hyperuricemia36363333
Hyperkalemia243192
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 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 ReactionVENCLEXTA
(N = 352)
All Grades (%)Grade ≥3 (%)
Blood and lymphatic system disorders
Neutropeniaa5045
Anemiaa3318
Thrombocytopeniaa2920
Lymphopeniaa117
Febrile neutropenia66
Gastrointestinal disorders
Diarrhea433
Nausea421
Abdominal paina183
Vomiting161
Constipation16<1
Mucositisa13<1
Infections and infestations
Upper respiratory tract infectiona361
Pneumoniaa148
Lower respiratory tract infectiona112
General disorders and administration site conditions
Fatiguea324
Edemaa222
Pyrexia18<1
Musculoskeletal and connective tissue disorders
Musculoskeletal paina292
Arthralgia12<1
Respiratory, thoracic, and mediastinal disorders
Cougha220
Dyspneaa131
Nervous system disorders
Headache18<1
Dizzinessa140
Skin and subcutaneous tissue disorders
Rasha18<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 AbnormalityVENCLEXTA
(N = 352)
All Gradesa (%)Grade 3 or 4 (%)
Hematology
Leukopenia8942
Neutropenia8763
Lymphopenia7440
Anemia7126
Thrombocytopenia6431
Chemistry
Hypocalcemia8712
Hyperglycemia677
Hyperkalemia595
AST increased533
Hypoalbuminemia492
Hypophosphatemia4511
Hyponatremia409
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]. 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]. 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]. 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]. 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 [see DOSAGE AND ADMINISTRATION].

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]. 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 ReactionVENCLEXTA + Azacitidine
(N = 283)
Placebo + Azacitidine
(N = 144)
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Gastrointestinal disorders
Nausea44235<1
Diarrheaa435333
Vomitingb30223<1
Stomatitisc181130
Abdominal paind18<1130
Blood and lymphatic system disorders
Febrile neutropenia42421919
Musculoskeletal and connective tissue disorders
Musculoskeletal paine362281
General disorders and administration site conditions
Fatiguef316232
Edemag27<1190
Vascular disorders
Hemorrhageh277243
Hypotensioni12583
Metabolism and nutrition disorders
Decreased appetitej25417<1
Skin and subcutaneous tissue disorders
Rashk251150
Infections and infestations
Sepsisl (excluding fungal)22221614
Urinary tract infectionm16696
Respiratory, thoracic and mediastinal disorders
Dyspnean184102
Nervous system disorders
Dizzinesso17<18<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 AbnormalityVENCLEXTA + AzacitidinePlacebo + Azacitidine
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Hematology
Neutrophils decreased98988881
Platelet decreased94889480
Lymphocytes decreased91717239
Hemoglobin decreased61575652
Chemistry
Bilirubin increased537404
Calcium decreased516399
Sodium decreased4614478
Alkaline phosphatase increased42129<1
Blood bicarbonate decreased31<1250
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 [see Clinical Studies]. 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 [see Clinical Studies]. 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 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 ReactionVENCLEXTA + 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
Nausea421310
Diarrhea283160
Vomiting25<1130
Abdominal paina15<193
Stomatitisb15160
Blood and lymphatic system disorders
Febrile neutropenia32322929
Infections and infestations
Pneumoniac29192121
Vascular Disorders
Hemorrhaged278161
Hypotensione11541
Musculoskeletal and connective tissue disorders
Musculoskeletal painf233180
General Disorders and Administration Site Conditions
Fatigueg222210
Nervous System Disorders
Headache11060
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 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 AbnormalityVENCLEXTA + Low-Dose CytarabinePlacebo + Low-Dose Cytarabine
All Grades (%)Grade 3 or 4 (%)All Grades (%)Grade 3 or 4 (%)
Hematology
Platelets decreased97959290
Neutrophils decreased95928271
Lymphocytes decreased92696524
Hemoglobin decreased63575754
Chemistry
Bilirubin increased617387
Albumin decreased616434
Potassium decreased56164214
Calcium decreased5384513
Glucose increased5213599
AST increased366371
Alkaline phosphatase increased341261
ALT increased304261
Sodium increased11361
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 [see Clinical Studies]. 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.

Read the entire FDA prescribing information for Venclexta (Venetoclax Tablets)

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