Venetoclax oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of venetoclax.
Drugs List
Therapeutic Indications
Uses
Leukaemia - acute myeloid
Leukaemia - chronic lymphocytic
Combination therapy with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).
Combination therapy with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.
Monotherapy treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor.
Monotherapy treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Combination therapy with a hypomethylating agent or low dose cytarabine is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
The treatment should be stopped at the point of disease progression or if it is no longer tolerated by the patient.
Adults
Chronic lymphocytic leukaemia (CLL)
Treatment over 5 weeks
Week 1: 20mg in the morning
Week 2: 50mg in the morning
Week 3: 100mg in the morning
Week 4: 200mg in the morning
Week 5 and beyond: 400mg in the morning
Acute myeloid leukaemia (AML)
Day 1: 100mg in the morning
Day 2: 200mg in the morning
Day 3: 400mg in the morning
Day 4 and beyond: 400mg in the morning when used in combination with a hypomethylating agent. Alternatively, 600mg in the morning when used in combination with low dose cytarabine.
Patients with Hepatic Impairment
Reduce dose by at least 50% throughout treatment in patients with severe hepatic impairment.
Additional Dosage Information
Missed Doses
If a dose is missed within 8 hours of the time it is usually taken, take the missed dose as soon as possible. If a dose is missed by more than 8 hours, the missed dose should not be taken and normal dosing schedule should be resumed the following day.
Recommended tumour lysis syndrome (TLS) prophylaxis based on tumour burden in patients with CLL
Low tumour burden (all LN less than 5cm and ALC less than 25 x 10 to the power of 9/L)
Oral hydration of 1.5L to 2L daily, 2 days prior to and during titration phase is recommended. It is also recommended to start allopurinol 2 to 3 days prior to initiation of venetoclax. Outpatients must have blood chemistries monitored 6 to 8 hours after initial dose and again after 24 hours if the patient is still at risk of TLS.
Medium tumour burden (any LN between 5cm and 10cm or ALC higher than or equal to 25 x 10 to the power of 9/L)
Oral hydration of 1.5L to 2L daily, 2 days prior to and during titration phase is recommended. Additional intravenous hydration may also be considered. It is also recommended to start allopurinol 2 to 3 days prior to initiation of venetoclax. Outpatients must have blood chemistries monitored 6 to 8 hours after initial dose and again after 24 hours if the patient is still at risk of TLS. Consider hospitalisation of patients with creatinine clearance less than 80ml/minute.
High tumour burden (any LN larger than 10cm or ALC higher than or equal to 25 x 10 to the power of 9/L and any LN equal to or larger than 5cm)
Oral hydration of 1.5L to 2L daily, 2 days prior to and during titration phase is recommended. Additional intravenous hydration is recommended at 150-200ml/hour as tolerated. It is also recommended to start allopurinol 2 to 3 days prior to initiation of venetoclax. Rasburicase can be considered if baseline uric acid is elevated.
Outpatients must have blood chemistries monitored 6 to 8 hours after initial dose and again after 24 hours if the patient is still at risk of TLS. Hospitalised patients must have blood chemistries monitored 4, 8 and 12 hours after initial dose and again after 24 hours if the patient is still at risk of TLS
Dose modification for tumour lysis syndrome (TLS) and re-occurrence of haematological and non-haematological toxicities in patients with CLL
Tumour lysis syndrome
In the event of blood chemistry changes or symptoms suggestive of TLS, withhold the next daily dose. If symptoms resolve within 48 hours of the last dose, restart at the same dose. If blood chemistry changes require more than 48 hours to resolve, start at a reduced dose. In the event of clinical TLS, restart at a reduced dose once resolved.
Grade 3 or Grade 4 non-haematologic toxicities
At the first occurrence, interrupt venetoclax. Once the toxicity has reduced to Grade 1 or baseline, treatment may be resumed at the same dose. No dose adjustments are necessary.
At subsequent occurrences, interrupt venetoclax. Follow dose reduction guidelines as listed below, restarting treatment after resolution.
Grade 3 neutropenia with infection or fever; or Grade 4 haematologic toxicities (except lymphopenia)
At the first occurrence, interrupt venetoclax. Granulocyte-colony stimulating factor (G-CSF) may be administered with venetoclax if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline, treatment may be restarted at the same dose.
At subsequent occurrences, interrupt venetoclax. Consider using G-CSF as clinically indicated. Follow dose reduction guidelines as listed below, restarting treatment after resolution.
Dose reduction for tumour lysis syndrome (TLS) and re-occurrence of haematological and non-haematological toxicities in patients with CLL
If evidence of tumour lysis syndrome, withhold the following days dose. If resolves within 1 to 2 days, resume at the same dose. If it takes more than 2 days, resume at a reduced dose of:
400mg reduced to 300mg once daily
300mg reduced to 200mg once daily
200mg reduced to 100mg once daily
100mg reduced to 50mg once daily
50mg reduced to 20mg once daily
20mg reduced to 10mg once daily
Dose reduction should be used for 1 week before re-titrating.
Consider discontinuation of treatment if decreasing to less than 100mg for over 2 weeks.
If dose interruption is longer than a week during the initial 5 weeks of dose titration or dose interruption is longer than 2 weeks when at 400mg daily, risk of TLS should be assessed to determine if re-initiation at a reduced dose is required.
Dose modifications for adverse reactions in patients with AML
Grade 4 neutropenia (absolute neutrophil count (ANC) lower than 500 per microlitre) with or without fever or infection; or grade 4 thrombocytopenia (platelet count less than 25 x 10 to the power 3 per microlitre)
Occurrence prior to achieving remission: Interruption of venetoclax dosing not required
First occurrence after achieving remission and lasting at least 7 days: Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine or low dose cytarabine and monitor blood counts. Administer granulocyte-colony stimulating factor (G-CSF) if clinically indicated for neutropenia. Upon resolution to grade 1 or 2, resume venetoclax dosing at the same dose in combination with azacitidine or decitabine or low dose cytarabine.
Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer: Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine or low dose cytarabine and monitor blood counts. Administer granulocyte-colony stimulating factor (G-CSF) if clinically indicated for neutropenia. Upon resolution to grade 1 or 2, resume venetoclax dosing at the same dose in combination with azacitidine or decitabine or low dose cytarabine, and reduce venetoclax duration by 7 days during each of the subsequent cycles.
Grade 3 or 4 non-haematologic toxicities
Interrupt venetoclax if not resolved with supportive care. Upon resolution to grade 1 or baseline level, resume venetoclax at the same dose.
Use with CYP3A inhibitor in CLL
Do not use with strong CYP3A inhibitors at initiation and during titration phase. The use with moderate CYP3A inhibitor is not recommended. If a moderate CYP3A must be used, reduce the initiation and titration phase doses by at least 50%.
After completion of titration phase, reduce the dose by at least 50%, on a steady daily dose, when used with moderate CYP3A inhibitors and reduce to 100mg or by 75% if used with strong CYP3A inhibitors. The dose may be further adjusted if needed. After the inhibitor has been stopped, use the previous dosage after 2 to 3 days.
Use with CYP3A inhibitor in AML
The use with strong CYP3A inhibitor is not recommended. If a strong CYP3A must be used, reduce the initiation and titration phase doses as below:
Day 1: 10mg
Day 2: 20mg
Day 3: 50mg
Day 4: 100mg or less
The use with moderate CYP3A inhibitor is not recommended. If a moderate CYP3A must be used, reduce the initiation and titration phase doses by at least 50%.
After completion of titration phase, reduce the dose by at least 50%, on a steady daily dose, when used with moderate CYP3A inhibitors and reduce to 100mg or by 75% if used with strong CYP3A inhibitors. The dose may be further adjusted if needed. After the inhibitor has been stopped, use the previous dosage after 2 to 3 days.
Contraindications
Children under 18 years
Breastfeeding
Leucocyte count above 25 x 10 to the power of 9/L - if treating AML
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Precautions and Warnings
Lymphocyte count above 25 x 10 to the power of 9/L
Dehydration
Moderate hepatic impairment
Renal impairment - creatinine clearance below 80ml/min
Administration of live vaccines is not recommended
Reduce dose in patients with severe hepatic impairment
Advise ability to drive/operate machinery may be affected by side effects
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Premedicate with a hypouricaemic agent
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Must be taken shortly before or during a meal
Staff: Not to be handled by pregnant staff
Monitor hepatic function prior to treatment
Monitor serum electrolytes before and during treatment
Monitor complete blood counts before each dose
Monitor patient closely during titration of dose
Monitor patient closely for signs and symptoms of toxicity
Monitor patients for signs of tumour lysis syndrome
Monitor renal function
Advise patients at risk of neutropenia to report any signs of infection
Suspend treatment and/or reduce dose if grade 3 or greater neutropenia
Suspend treatment and/or reduce dose in grade 3 non-haematological toxicity
Suspend treatment and/or reduce dose in grade 4 haematological toxicity
Suspend treatment if tumour lysis syndrome occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Advise patient Seville (sour) orange products may increase plasma level
Advise patient to avoid star fruit
Female: Contraception required during and at least 30 days after treatment
Remind patient of importance of carrying Alert Card with them at all times
Tumour lysis syndrome
Tumour lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax, even after a single 20mg dose. Patients with risk factors for tumour lysis syndrome (circulating blasts, high burden of leukaemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase (LDH) levels, splenomegaly in chronic lymphocytic leukaemia or reduced renal function) should have increased laboratory monitoring and a reduced venetoclax starting dose considered. Prior to initiating venetoclax, patients should be assessed for risk of tumour lysis syndrome by performing a tumour burden assessment and radiographic evaluation (CT scan) and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Blood chemistries (potassium, uric acid, phosphorus, calcium and creatinine) should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed. When restarting venetoclax, dose modification guidance should be followed.
Prophylaxis measures for acute myeloid leukaemia
All patient should have a white blood cell count less than 25 x 10 to the power 9/L prior to initiation of treatment with venetoclax and cytoreduction prior to treatment may be required.
Pregnancy and Lactation
Pregnancy
Venetoclax is contraindicated during pregnancy.
The manufacturer does not recommend using venetoclax during pregnancy. Animal studies have shown teratogenic effects. Human data is limited and as such a potential risk cannot be ruled out.
Lactation
Venetoclax is contraindicated during breastfeeding.
Use of venetoclax when breastfeeding is contraindicated by the manufacturer. The presence of venetoclax in human breast milk and its effects on exposed infants are unknown therefore the risk to the breast-fed infant cannot be excluded.
Side Effects
Abdominal pain
Anaemia
Arthralgia
Asthenia
Cholecystitis
Cholelithiasis
Constipation
Decreased appetite
Diarrhoea
Dizziness
Dyspnoea
Fatigue
Febrile neutropenia
Haemorrhage
Headache
Hyperkalaemia
Hyperphosphataemia
Hyperuricaemia
Hypocalcaemia
Hypokalaemia
Hypotension
Increase in blood urea or creatinine
Infection
Lymphopenia
Nausea
Neutropenia
Nightmares
Pneumonia
Reduced neutrophil count
Sepsis
Stomatitis
Syncope
Thrombocytopenia
Tumour lysis syndrome
Upper respiratory tract infection
Urinary tract infections
Vomiting
Weight loss
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: June 2021
Reference Sources
Summary of Product Characteristics: Venclyxto 10 mg film coated tablets. AbbVie Ltd. Revised October 2022.
Summary of Product Characteristics: Venclyxto 50 mg film coated tablets. AbbVie Ltd. Revised October 2022.
Summary of Product Characteristics: Venclyxto 100 mg film coated tablets. AbbVie Ltd. Revised October 2022.
Summary of Product Characteristics: Venclyxto 10 mg, 50 mg, 100 mg film coated tablets (Northern Ireland). AbbVie Ltd. Revised May 2021.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 11 January 2023.
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