Venetoclax

Venetoclax is used for: Chronic lymphocytic leukaemia, Small lymphocytic lymphoma

Oral Chronic lymphocytic leukaemia, Small lymphocytic lymphoma Adult: Dose ramp-up phase Administer dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg Ramp-up dosing schedule designed to gradually reduce tumor burden and decrease risk of tumor lysis syndrome Week 1: 20 mg PO qDay Week 2: 50 mg PO qDay Week 3: 100 mg PO qDay Week 4: 200 mg PO qDay Week 5 and beyond: 400 mg PO qDay Monotherapy 400 mg PO qDay after completing the 5-week dose ramp-up schedule Continue until disease progression or unacceptable toxicity Combination with obinutuzumab Cycle 1 Day 1: Obinutuzumab 100 mg IV Day 2: Obinutuzumab 900 mg IV Days 8 and 15: Obinutuzumab 1000 mg IV Day 22: Start venetoclax according to 5-week ramp up schedule Cycle 2 Day 1: Obinutuzumab 1000 mg IV Day 28: After completing the ramp-up phase on Cycle 2 Day 28, continue venetoclax 400 mg qDay from Cycle 3 Day 1 until Cycle 12 Day 28 Cycles 3-6 Day 1: Obinutuzumab 1000 mg IV Days 1-28: Continue venetoclax 400 mg PO qDay Cycles 7-12 Days 1-28: Continue venetoclax 400 mg PO qDay Combination with rituximab Venetoclax Complete 5-week ramp-up dosing to reach 400 mg PO qDay Continue venetoclax 400 mg PO qDay for 24 months from Cycle 1 Day 1 of rituximab Rituximab Initiate 375 mg/m² IV after patient has received venetoclax 400 mg/day x 7 days (ie, this will be Day 1 of Cycle 1) 500 mg/m² IV on Day 1 for Cycles 2-6 Acute Myeloid Leukemia Indicated in combination with azacitidine or decitabine or low-dose cytarabine for treatment in adults (?75 years) who are newly-diagnosed acute myeloid leukemia (AML) or who have comorbidities that preclude use of intensive induction chemotherapy Venetoclax dosing depends on the combination agent Dose ramp-up phase Day 1: 100 mg PO qDay Day 2: 200 mg PO qDay Day 3: 400 mg PO qDay Day 4 and beyond (in combination with decitabine or azacitidine): 400 mg PO qDay Day 4 and beyond (in combination with low-dose cytarabine): 600 mg PO qDay In combination with decitabine, azacitidine, or low-dose cytarabine: Continue until disease progression or unacceptable toxicity Hepatic impairment Mild or moderate (Child-Pugh A or B): No dosage adjustment; monitor more frequently for signs of toxicity or adverse reactions during initiation and ramp-up phases Severe (Child-Pugh C): Reduce venetoclax dose by 50%; monitor

Renal impairment Mild or moderate (CrCl ?15 mL/min): No dosage adjustment necessary Severe (CrCl <15 mL/min) or patients on dialysis: Recommended dose has not been determined

Should be taken with food.

Concomitant use with strong CYP3A4 inhibitors at initiation and during dose titration phase. Administration of live vaccines.

Therapy can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL; changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following first dose and at each dose increase; TLS, including fatal cases, has been reported after a single 20 mg dose Neutropenia frequently reported; monitor complete blood cell counts throughout treatment period Fatal and serious infections such as pneumonia and sepsis have occurred; monitor patients closely for signs and symptoms of infection and treat promptly; withhold therapy for Grade 3 and higher infection Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden when treated with venetoclax The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy; splenomegaly may also increase risk of TLS in patients with CLL/SLL Do not administer live attenuated vaccines prior to, during, or after treatment until B-cell recovery occurs; safety and efficacy of immunization with live attenuated vaccines during or following therapy have not been studied; advise patients that vaccinations may be less effective Based on its mechanism of action and findings in animals, may cause embryofetal harm when administered to a pregnant woman

Pregnancy There are no available human data on use in pregnant women; based on its mechanism of action and findings in animals, may cause embryofetal harm when administered to a pregnant woman Females of reproductive potential should undergo pregnancy testing before initiation Animal studies In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily Fertility and contraception Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last dose Male fertility may be compromised by treatment Lactation Unknown if distributed in human breast milk; advise nursing women to discontinue breastfeeding during treatment and for at least one week after last dose

Decreased serum concentration and efficacy with moderate to strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin). Potentially Fatal: Increased serum concentration and risk of TLS with strong CYP3A4 inhibitors (e.g. itraconazole, clarithromycin, ritonavir). May diminish therapeutic effect of live vaccines.

Side effects of Venetoclax : >10% (Combination with rituximab) Leukopenia (89%) Lymphopenia (87%) Neutropenia (65-86%) Neutropenia, Grade 3 or 4 (62-64%) Hypocalcemia (62%) Hypophosphatemia (57%) Lymphopenia, Grade 3 or 4 (56%) Leukopenia, Grade 3 or 4 (46%) Diarrhea (43%) Increased AST/SGOT (46%) Diarrhea (40%) Upper respiratory tract infection (39%) Hyperuricemia (36%) Increased alkaline phosphatase (35%) Hyperbilirubinemia (33%) Hyponatremia (30%) Hypokalemia (29%) Hyperkalemia (24%) Hypernatremia (24%) Nausea (21%) Musculoskeletal pain (19%) Lower respiratory tract infection (18%) Anemia (16%) Thrombocytopenia (15%) Constipation (14%) Hypophosphatemia, Grade 3 or 4 (14%) Abdominal pain (13%) Rash (13%) Headache (11%) Insomnia (11%) >10% (Monotherapy) Neutropenia (50%) Neutropenia, Grade 3 or 4 (45%) Nausea (42%) Upper respiratory tract infection (36%) Anemia (33%) Fatigue (32%) Thrombocytopenia (29%) Edema (22%) Thrombocytopenia, Grade 3 or 4 (20%) Anemia, Grade 3 or 4 (18%) Abdominal pain (18%) Pyrexia (18%) Vomiting (16%) Constipation (16%) Mucositis (13%) Lymphopenia (11%) 1-10% (Combination with rituximab) Mucositis (10%) Pneumonia (10%) Vomiting (8%) Lymphopenia, Grade 3 or 4 (7%) Hyponatremia, Grade 3 or 4 (6%) Hypokalemia, Grade 3 or 4 (6%) Hypocalcemia, Grade 3 or 4 (5%) Febrile neutropenia (4%) Hyperbilirubinemia, Grade 3 or 4 (4%) Diarrhea, Grade 3 or 4 (3%) TLS, Grade 3 or 4 (3%) Hyperkalemia, Grade 3 or 4 (3%) Upper respiratory tract infection, Grade 3 or 4 (2%) Lower respiratory tract infection, Grade 3 or 4 (2%) Increased AST/SGOT (2%) Hypernatremia, Grade 3 or 4 (1%) Musculoskeletal pain, Grade 3 or 4 (1%) Increased alkaline phosphatase, Grade 3 or 4 (1%) 1-10% (Monotherapy) Febrile neutropenia (6%) Fatigue, Grade 3 or 4 (4%) Abdominal pain, Grade 3 or 4 (3%) Diarrhea, Grade 3 or 4 (3%) Edema, Grade 3 or 4 (2%) Nausea, Grade 3 or 4 (1%) Vomiting, Grade 3 or 4 (1%) Upper respiratory tract infection, Grade 3 or 4 (1%) <1% Monotherapy Constipation, Grade 3 or 4 Mucositis, Grade 3 or 4 Pyrexia, Grade 3 or 4

Venetoclax selectively inhibits B-cell lymphoma-2 (BCL-2), an anti-apoptic protein, resulting to displacement of pro-apoptotic proteins like BIM, initiation of mitochondrial outer membrane permeabilisation, restoration of the apoptotic process or programmed cell death.