Venetoclax

Registered South African indications:

• Chronic lymphocytic leukaemia (CLL)

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Immunisation with live attenuated viral and/or bacterial vaccines
  - During treatment and thereafter until B-cell recovery
• Coadministration with strong CYP3A inhibitors at initiation and during the dose-titration phase
• Coadministration with moderate or strong CYP3A4 inducers
• Coadministration with preparations containing St. John’s wort

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with strong CYP3A inhibitors at initiation and during the dose-titration phase (for the indication of CLL)
• Coadministration with preparations containing St. John’s wort

Cautions

South African manufacturer recommendations

• Women of childbearing potential and for 30 days after ending treatment with venetoclax (unless on highly effective contraceptive measures)
• Males of reproductive potential
• Renal impairment
  - CrCl<80ml/min
  - Severe (CrCl<30ml/min) or dialysis
• Moderate to severe hepatic impairment
• Changes in electrolytes
• Risk factors of TLS
  - High tumour burden (e.g. any lymph node with a diameter ≥5cm or high ALC ≥25 x 10⁹/l)
  - Renal impairment (CrCl<80ml/min)
  - Coadministration with moderate CYP3A inhibitors
  - Coadministration with P-gp inhibitors
  - Coadministration with BCRP inhibitors
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential and for 30 days after ending treatment with venetoclax (unless on highly effective contraceptive measures)
• Breastfeeding
• Males of reproductive potential
• Renal impairment
  - CrCl<80ml/min
  - Severe (CrCl 15-29ml/min)
  - CrCl<15ml/min or dialysis
• Moderate to severe hepatic impairment
• Changes in electrolytes
• Risk factors of TLS
  - Renal impairment
  - High tumour burden
  - Splenomegaly in CLL
  - Coadministration with moderate CYP3A inhibitors
  - Coadministration with P-gp inhibitors
  - Coadministration with BCRP inhibitors
• Immunisation with live attenuated vaccines
  - During treatment and thereafter until B-cell recovery
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment with venetoclax should be initiated and supervised by a medical practitioner experienced in the use of anticancer medicines

Used for the treatment of

• Chronic lymphocytic leukaemia (CLL) (Additional agent may be required)
  - In combination with obinutuzumab in those with previously untreated CLL
  - In combination with rituximab in those with relapsed or refractory chronic lymphocytic leukaemia (R/R CLL)
  - As monotherapy in those with R/R CLL

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Consult specialist for dosages and regimens

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Venetoclax film-coated tablets are for oral use. Patients should be instructed to swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal in order to avoid a risk for lack of efficacy. The tablets should not be chewed, crushed, or broken before swallowing

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During the dose-titration phase, venetoclax should be taken in the morning to facilitate laboratory monitoring

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International manufacturer recommendations

Treatment with venetoclax should be initiated and supervised by a physician experienced in the use of anticancer medicinal products

Used for the treatment of

• Chronic lymphocytic leukaemia (CLL)
  - In combination with obinutuzumab in those with previously untreated CLL
  - In combination with rituximab in those with CLL who have received at least one prior therapy
  - As monotherapy in the presence of 17p deletion or TP53 mutation in those who are unsuitable for or have failed a B-cell receptor pathway inhibitor
  - As monotherapy in the absence of 17p deletion or TP53 mutation in those who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor
• Newly diagnosed acute myeloid leukaemia (AML) (Additional agent may be required)
  - In combination with a hypomethylating agent or low-dose cytarabine in those who are ineligible for intensive chemotherapy

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Consult specialist for dosages and regimens

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Patients treated with venetoclax may develop tumour lysis syndrome (TLS)
See additional prescribing points

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Venetoclax film-coated tablets are for oral use. Patients should be instructed to swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal in order to avoid a risk for lack of efficacy. The tablets should not be chewed, crushed, or broken before swallowing

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During the dose-titration phase, venetoclax should be taken in the morning to facilitate laboratory monitoring

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Pregnant women should not be treated with venetoclax
• Based on embryo-foetal toxicity studies in animals, there is a potential risk of serious harm to the foetus when administered to pregnant women
• There are no adequate and well controlled data from the use of venetoclax in pregnant women. Studies in animals have shown reproductive toxicity
• Venetoclax should not be used during pregnancy and in women of childbearing potential not using highly effective contraception
• Women should avoid becoming pregnant while taking venetoclax and for at least 30 days after ending treatment
• Therefore, women of childbearing potential must use highly effective contraceptive measures while taking venetoclax and for 30 days after stopping treatment
• It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• Based on embryo-foetal toxicity studies in animals, venetoclax may harm the foetus when administered to pregnant women
• There are no adequate and well-controlled data from the use of venetoclax in pregnant women. Studies in animals have shown reproductive toxicity
• Venetoclax is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception
• Women should avoid becoming pregnant while taking venetoclax and for at least 30 days after ending treatment
• Therefore, women of childbearing potential must use highly effective contraceptive measures while taking venetoclax and for 30 days after stopping treatment
• It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Women on treatment with venetoclax should not breastfeed their infants
• It is unknown whether venetoclax or its metabolites are excreted in human milk and harm to the breastfed infant cannot be excluded
• Breastfeeding should be discontinued during treatment with venetoclax

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether venetoclax or its metabolites are excreted in human milk
• A risk to the breastfeeding child cannot be excluded
• Breastfeeding should be discontinued during treatment with venetoclax

Fertility

South African manufacturer recommendations

• No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity in dogs at clinically relevant exposures, male fertility may be compromised by treatment with venetoclax
• It is unknown whether fertility would be restored to pre-treatment status after stopping venetoclax. Before starting treatment, counselling on sperm storage should be considered in male patients

International manufacturer recommendations

• No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity in dogs at clinically relevant exposures, male fertility may be compromised by treatment with venetoclax
• Before starting treatment, counselling on sperm storage may be considered in some male patients

Renal Impairment

South African manufacturer recommendations

• Mild: CrCl≥80ml/min: No dose adjustment recommended 
• Mild to moderate: CrCl≥30-<80ml/min: Caution; no dose adjustment recommended
  May require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose titration phase (See additional prescribing points)
• Severe: CrCl<30ml/min or dialysis: Caution; no information available 

International manufacturer recommendations

• Mild: CrCl≥80ml/min: No dose adjustment recommended 
• Mild to moderate: CrCl≥30-<80ml/min: Caution; no dose adjustment recommended 
  May require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase (See additional prescribing points)
• Severe: CrCl 15-29ml/min: Caution; no dose adjustment recommended 
  Only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS
• CrCl<15ml/min or dialysis: Caution; no information available 

Hepatic Impairment

• Mild: No dose adjustment recommended 
• Moderate: Caution; no dose adjustment recommended 
  Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity at initiation and during the dose-titration phase
• Severe: Caution; dose adjustment recommended 
  A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment
  These patients should be monitored more closely for signs of toxicity

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue
• Dizziness
• Syncope
• Headache

Cardiovascular Disorders

• Hypotension
• Haemorrhage

Respiratory Disorders

• Pneumonia
• Upper respiratory tract infection
• Dyspnoea

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Constipation
• Decreased appetite
• Stomatitis
• Abdominal pain

Hepatobiliary Disorders

• Cholecystitis
• Cholelithiasis
• Increased blood bilirubin

Genitourinary Disorders

• Urinary tract infection
• Increased blood creatinine
• Acute renal failure

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hypokalaemia
• Hyperphosphataemia
• Hypocalcaemia
• Tumour lysis syndrome
  - Fever
  - Chills
  - Nausea and vomiting
  - Confusion
  - Shortness of breath
  - Seizures
  - Irregular heartbeat
  - Dark or cloudy urine
  - Unusual tiredness
  - Muscle or joint pain
  - Abdominal pain and distension
• Hyperuricaemia
• Decreased weight

Musculoskeletal Disorders

• Arthralgia

Immune, Blood and Lymphatic System Disorders

• Sepsis
• Neutropenia
• Anaemia
• Lymphopenia
• Febrile neutropenia
• Thrombocytopenia
• Bacteraemia

Others

• Fatal events

• Strong CYP3A inhibitors
• Itraconazole
• Ketoconazole
• Posaconazole
• Voriconazole
• Clarithromycin
• Ritonavir
• Moderate CYP3A inhibitors
• Ciprofloxacin
• Diltiazem
• Erythromycin
• Fluconazole
• Verapamil
• P-gp inhibitors
• Rifampicin
• BCRP inhibitors
• BCRP substrates
• Digoxin
• Dabigatran
• OATP substrate
• Statins
• Everolimus
• Sirolimus
• Strong CYP3A inducers
• Carbamazepine
• Phenytoin
• Moderate CYP3A inducers
• Bosentan
• Efavirenz
• Etravirine
• Modafinil
• Nafcillin
• Azithromycin
• Bile acid sequestrants
• Warfarin
• Live attenuated vaccines

Other interactions

• St. John's wort
• Grapefruit products
• Seville oranges
• Starfruit (carambola)

• Full blood count with differential
• Blood chemistries
  - Potassium
  - Uric acid
  - Phosphorus
  - Calcium
  - Creatinine
• Hepatic function
• Renal function
• Radiographic evaluation of tumour burden
  - CT scan
• Hepatitis B virus screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to surface antigen
• Risk assessment of past or chronic HBV infection

Specific cases may require

• Pregnancy status

Additional observations

• Risk evaluation for tumour lysis syndrome (TLS)
  - Those at high risk of tumour lysis syndrome
• Adverse reactions
  - In those with hepatic impairment
• Adherence
• Signs and symptoms of infection
• Signs and symptoms of TLS
  - Fever
  - Chills
  - Nausea and vomiting
  - Confusion
  - Shortness of breath
  - Seizures
  - Irregular heartbeat
  - Dark or cloudy urine
  - Unusual tiredness
  - Muscle or joint pain
  - Abdominal pain and distension
• For those on statins
  - Statin-related toxicity

Tumour lysis syndrome (TLS)

• Tumour lysis syndrome, including fatal events, has occurred in patients with CLL with high tumour burden when treated with venetoclax
• Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS in the initial 5-week dose-titration phase
• Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose increase
• The risk of TLS is a continuum based on multiple factors, including comorbidities. Patients with high tumour burden (e.g., any lymph node with a diameter ≥5cm or high absolute lymphocyte count [ALC≥25 x 10 9 /l]) are at greater risk of TLS when initiating venetoclax
• Risk factors for TLS also include splenomegaly in CLL (international manufacturer recommendations)
• Reduced renal function (CrCl<80 ml/min) further increases the risk. The risk may decrease as tumour burden decreases with venetoclax treatment
• All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics
• Blood chemistries should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed. More intensive measures (intravenous hydration, frequent monitoring, hospitalisation) should be employed as overall risk increases. The instructions for “Prevention of tumour lysis syndrome” should be followed

Prevention of tumour lysis syndrome

• Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation (e.g., CT scan), must be performed for all patients. Blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) should be assessed and pre-existing abnormalities corrected. The prophylaxis measures listed below should be followed. More intensive measures should be employed as overall risk increases

Hydration

• Patients should be adequately hydrated during the dose-titration phase to reduce the risk of TLS. Patients should be instructed to drink plenty of water daily starting 2 days before and throughout the dose-titration phase
• Patients should be particularly instructed to drink 1.5-2.0L of water daily, 2 days prior to and the days of dosing at initiation and each subsequent dose increase. Intravenous fluids should be administered as indicated based on overall risk of TLS or for those who cannot maintain an adequate level of oral hydration

Anti-hyperuricaemic agents

• Anti-hyperuricaemic medicines should be administered 2-3 days prior to starting treatment with venetoclax in patients with high uric acid levels or at risk of TLS and may be continued through the titration phase

Laboratory assessments

• Pre-dose: For all patients, blood chemistries should be assessed prior to the initial dose to evaluate renal function and correct pre-existing abnormalities. Blood chemistries should be reassessed prior to each subsequent dose increase during the titration phase.
• Post-dose: For patients at risk of TLS, blood chemistries should be monitored at 6-8 hours and at 24 hours after the first dose of venetoclax. Electrolyte abnormalities should be corrected promptly. The next venetoclax dose should not be administered until the 24-hour blood chemistry results have been evaluated. The same monitoring schedule should be followed at the start of the 50mg dose and then for patients who continue to be at risk, at subsequent dose increases

Hospitalisation

• Based on medical practitioner assessment, some patients, especially those at greater risk of TLS, may require hospitalisation on the day of the first dose of venetoclax for more intensive prophylaxis and monitoring during the first 24 hours
• Hospitalisation should be considered for subsequent dose increases based on reassessment of risk

Dose modifications for tumour lysis syndrome

• If a patient experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax dose should be withheld. If resolved within 24-48 hours of last dose, treatment with venetoclax can be resumed at the same dose. For events of clinical TL S or blood chemistry changes requiring more than 48 hours to resolve, treatment should be resumed at a reduced dose. When resuming treatment after interruption due to TLS, the instructions for prevention of TLS should be followed

Dose modifications for other toxicities

• Treatment with venetoclax should be withheld for any grade 3 or 4 non-haematological toxicities, grade 3 or 4 neutropenia with infection or fever, or grade 4 haematological toxicities, except lymphopenia
• Once the toxicity has resolved to grade 1 or baseline level (recovery), therapy with venetoclax may be restarted at the same dose
• If the toxicity recurs, and for any subsequent occurrences, the dose reduction guidelines should be followed when resuming treatment with venetoclax following resolution
• A larger dose reduction may occur at the discretion of the medical practitioner. For patients who require dose reductions to less than 100mg for more than 2 weeks, discontinuation of venetoclax should be considered

Dose modifications for use with CYP3A inhibitors

• Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation and during the dose titration phase and for other toxicities
• Patients should be monitored more closely for signs of toxicities and the dose may need to be further adjusted. The venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2-3 days after discontinuation of the inhibitor

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Consult specialist for dosages and regimens

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Missed dose

• If a patient misses a dose of venetoclax within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible on the same day. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the following day
• If a patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time the following day

Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL (chronic lymphocytic leukaemia) and AML (acute myeloid leukaemia) cells where it mediates tumour cell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3-binding groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non-clinical studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL-2.

Film-coated tablet 10mg

• Venclexta  (AbbVie) originator

Film-coated tablet 50mg

• Venclexta  (AbbVie) originator

Film-coated tablet 100mg

• Venclexta  (AbbVie) originator