venetoclax: prescribing information – dosing, contraindications, interactions, side effects

Venclyxto is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL):
• in combination with acalabrutinib with or without obinutuzumab
• in combination with obinutuzumab (see section 5.1)
• in combination with ibrutinib

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the 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, or
- in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Treatment with venetoclax should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients treated with venetoclax may develop tumour lysis syndrome (TLS). Information described in this section, including risk assessment, prophylactic measures, dose-titration schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.

Posology

Chronic lymphocytic leukaemia

Dose-titration schedule

The starting dose is 20 mg of venetoclax once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose of 400 mg as shown in Table 1.

Table 1: Dose increase schedule in patients with CLL

Week
Venetoclax daily dose
20 mg
50 mg
100 mg
200 mg
400 mg

The 5-week dose-titration schedule is designed to gradually reduce tumour burden (debulk) and decrease the risk of TLS.

Venetoclax in combination with acalabrutinib with or without obinutuzumab

Treatment with venetoclax in combination with acalabrutinib with or without obinutuzumab should continue until disease progression, unacceptable toxicity or completion of 14 cycles (each cycle is 28 days).

Administer acalabrutinib 100 mg orally on Cycle 1 Day 1 approximately every 12 hours for a total of 14 cycles of treatment. Each cycle is 28 days.

Start the 5-week venetoclax dose-titration schedule (Table 1) on Cycle 3 Day 1. After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily until the last day of Cycle 14.

If venetoclax is given in combination with acalabrutinib and obinutuzumab, administer obinutuzumab 100 mg on Cycle 2 Day 1, followed by 900 mg, which may be administered on Day 1 or Day 2.
Administer 1000 mg on Days 8 and 15 of Cycle 2 and on Day 1 of Cycles 3 to 7. Obinutuzumab is administered for a total of 6 cycles.

Venetoclax in combination with obinutuzumab

Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent.

Administer obinutuzumab 100 mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles.

Start the 5-week venetoclax dose-titration schedule (see Table 1) on Cycle 1 Day 22 and continue through Cycle 2 Day 28.

After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12.

Venetoclax in combination with ibrutinib

Start ibrutinib (420 mg once daily) as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of venetoclax in combination with ibrutinib. Beginning on Cycle 4 Day 1, administer venetoclax according to the dose-titration schedule (see Table 1). After completing the dose-titration schedule, patients should continue venetoclax 400 mg once daily in combination with ibrutinib 420 mg orally once daily to the last day of Cycle 15.

Refer to the ibrutinib Summary of Product Characteristics for additional information.

Post-titration dose for venetoclax in combination with rituximab

The recommended dose of venetoclax in combination with rituximab is 400 mg once daily (see section 5.1 for details of the combination regimen).

Administer rituximab after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg venetoclax for 7 days.

Venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab (see section 5.1).

Post-titration dose for venetoclax monotherapy

The recommended dose of venetoclax is 400 mg once daily. Treatment is continued until disease progression or no longer tolerated by the patient.

Acute myeloid leukaemia

The recommended venetoclax dosing schedule (including dose-titration) is shown in Table 2.

Table 2: Dose increase schedule in patients with AML

Day
Venetoclax daily dose
100 mg
200 mg
3 and beyond
400 mg

Azacitidine should be administered at 75 mg/m2 of body surface area (BSA) either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1.

Decitabine should be administered at 20 mg/m2 of BSA intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1.

Venetoclax dosing may be interrupted as needed for management of hematologic toxicities and blood count recovery (see Table 6).

Venetoclax, in combination with a hypomethylating agent, should be continued until disease progression or unacceptable toxicity is observed.

Prevention of tumour lysis syndrome (TLS)

Patients treated with venetoclax may develop TLS. The appropriate section below should be referred to for specific details on management by disease indication.

Chronic lymphocytic leukaemia

Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS in the initial 5-week dose-titration phase in all patients with CLL, regardless of tumour burden and other patient characteristics. 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. Patient- specific factors for level of TLS risk should be assessed and prophylactic hydration and anti-hyperuricaemics should be provided to patients prior to first dose of venetoclax to reduce risk of TLS.

The risk of TLS is a continuum based on multiple factors, including comorbidities, particularly reduced renal function (creatinine clearance [CrCl] <80ml/min), and tumour burden. Splenomegaly may contribute to the overall TLS risk. The risk may decrease as tumour burden decreases with venetoclax treatment (see section 4.4).

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.

Table 3 below describes the recommended TLS prophylaxis and monitoring during venetoclax treatment based on tumour burden determination from clinical study data (see section 4.4). In addition, all patient comorbidities should be considered for risk-appropriate prophylaxis and monitoring, either outpatient or in hospital.

Table 3: Recommended TLS prophylaxis based on tumour burden in patients with CLL

Tumour burden
Prophylaxis
Blood chemistry monitoringc,d

Hydrationa
Anti- hyperuricaemicsb
Setting and frequency of assessments
Low
All LN <5 cm
AND
ALC <25 x109/L
Oral
(1.5-2 L)
Allopurinol
Outpatient
• For first dose of
20 mg and 50 mg:
Pre-dose, 6 to 8 hours,
24 hours
• For subsequent dose increases: Pre-dose
Medium
Any LN 5 cm to
<10 cm
OR
ALC ≥25 x109/L
Oral
(1.5-2 L) and consider additional intravenous
Allopurinol
Outpatient
• For first dose of
20 mg and 50 mg:
Pre-dose, 6 to 8 hours,
24 hours
• For subsequent dose increases: Pre-dose

• For first dose of
20 mg and 50 mg:
Consider hospitalisation for patients with CrCl
<80ml/min; see below for monitoring in hospital
High
Any LN ≥10 cm
OR
ALC ≥25 x109/L
AND any LN ≥5 cm
Oral (1.5-2 L) and intravenous
(150-200 ml/hr as tolerated)
Allopurinol;
consider rasburicase if baseline uric acid is elevated
In hospital
• For first dose of
20 mg and 50 mg:
Pre-dose, 4, 8, 12 and
24 hours
Outpatient
• For subsequent dose increases: Pre-dose, 6 to 8 hours, 24 hours
ALC = absolute lymphocyte count; CrCl = creatinine clearance; LN = lymph node.
aInstruct patients to drink water daily starting 2 days before and throughout the dose-titration phase, specifically prior to and on the days of dosing at initiation and each subsequent dose increase. Administer intravenous hydration for any patient who cannot tolerate oral hydration.
bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax.
cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
dAt subsequent dose increases, monitor blood chemistries at 6 to 8 hours and at 24 hours for patients who continue to be at risk of TLS.

Dose modifications for tumour lysis syndrome and other toxicities

Chronic lymphocytic leukaemia

Dosing interruption and/or dose reduction for toxicities may be required. See Table 4 and Table 5 for recommended dose modifications for toxicities related to venetoclax.

Refer to the prescribing information of each of the medicinal products used in combination with venetoclax for additional information for management of toxicities.

Table 4: Recommended venetoclax dose modifications for toxicitiesa in CLL

Event
Occurrence
Action
Tumour lysis syndrome
Blood chemistry changes or symptoms suggestive of TLS
Any
Withhold the next day’s dose. If resolved within
24 to 48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 5).
For any events of clinical TLS,b resume at a reduced dose following resolution (see Table 5).
Non-haematologic toxicities

Grade 3 or 4 non- haematologic toxicities
1st occurrence
Interrupt venetoclax.
Once the toxicity has resolved to Grade 1 or baseline level, venetoclax therapy may be resumed at the same dose. No dose modification is required.
2nd and subsequent occurrences
Interrupt venetoclax.
Follow dose reduction guidelines in Table 5 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
Haematologic toxicities
Grade 3 neutropenia with infection or fever; or
Grade 4 haematologic toxicities (except lymphopenia)
1st occurrence
Interrupt venetoclax.
To reduce the infection risks associated with neutropenia, granulocyte-colony stimulating factor (G-CSF) may be administered with venetoclax if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline level, venetoclax therapy may be resumed at the same dose.
2nd and subsequent occurrences
Interrupt venetoclax.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines in Table 5 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks.
aAdverse reactions were graded using NCI CTCAE version 4.0.
bClinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or seizures and/or sudden death (see section 4.8).

Table 5: Dose modification for TLS and other toxicities for patients with CLL

Dose at interruption
(mg)

Restart dose
(mga) aThe modified dose should be continued for 1 week before increasing the dose.

For patients who have had a dosing interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks after completing the dose-titration phase, TLS risk should be reassessed to determine if restarting at a reduced dose is necessary (e.g., all or some levels of the dose-titration; see Table 5).

Acute myeloid leukaemia

The venetoclax daily dose-titration is 3 days with azacitidine or decitabine (see Table 2).

Prophylaxis measures listed below should be followed:
All patients should have white blood cell count <25 × 109/l prior to initiation of venetoclax and cytoreduction prior to treatment may be required.

All patients should be adequately hydrated and receive anti-hyperuricaemic agents prior to initiation of first dose of venetoclax and during dose-titration phase.

Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with venetoclax.

Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during titration and 24 hours after reaching final dose.

For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukaemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing venetoclax starting dose.

Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. Dose modifications of venetoclax for adverse reactions are provided in Table 6.

Table 6: Recommended dose modifications for adverse reactions in AML

Adverse Reaction
Occurrence
Dosage Modification
Haematologic Adverse Reactions
Grade 4 neutropenia
(ANC < 500/microlitre) with or without fever or infection; or grade 4 thrombocytopenia (platelet count <25 × 103/microlitre) Occurrence prior to achieving remissiona In most instances, do not interrupt venetoclax in combination with azacitidine or decitabine due to cytopenias prior to achieving remission.
First occurrence after achieving remission and lasting at least 7 days
Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine 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 at the same dose in combination with azacitidine or decitabine.
Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine and monitor blood counts. Administer G-CSF if clinically indicated for neutropenia.
Upon resolution to grade 1 or 2, resume venetoclax at the same dose in combination with azacitidine or decitabine, and reduce venetoclax duration by 7 days during each of the subsequent cycles, such as 21 days instead of 28 days.
Refer to the azacitidine prescribing information for additional information.

Adverse Reaction
Occurrence
Dosage Modification
Non-Hematologic Adverse Reactions
Grade 3 or 4 non- hematologic toxicities
Any occurrence

Interrupt venetoclax if not resolved with supportive care.
Upon resolution to grade 1 or baseline level, resume venetoclax at the same dose.
aConsider bone marrow evaluation.

Dose modifications for use with CYP3A inhibitors

Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during the dose-titration phase and for other toxicities (see section 4.5).

In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors is contraindicated at initiation and during the dose-titration phase (see sections 4.3, 4.4, and 4.5).

In all patients, if a CYP3A inhibitor must be used, follow the recommendations for managing drug- drug interactions summarized in Table 7. 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 to 3 days after discontinuation of the inhibitor (see sections 4.3, 4.4 and 4.5).

Table 7: Management of potential venetoclax interactions with CYP3A inhibitors

Inhibitor
Phase
CLL
AML
Strong CYP3A inhibitor
Initiation and dose- titration phase
Contraindicated
Day 1 – 10 mg
Day 2 – 20 mg
Day 3 – 50 mg
Day 4 – 100 mg or less
Steady daily dose
(After dose-titration phase)
Reduce the venetoclax dose to 100 mg or less
(or by at least 75% if already modified for other reasons)
Moderate CYP3A inhibitora
All
Reduce the venetoclax dose by at least 50% aIn patients with CLL, avoid concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during the dose-titration phase. Consider alternative medicinal products or reduce the venetoclax dose as described in this table.

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.

Special populations

Elderly

No specific dose adjustment is required for elderly patients (aged ≥65 years) (see section 5.1).

Renal impairment

Patients with reduced renal function (CrCl <80 ml/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase (see “Prevention of tumour lysis syndrome (TLS)” above). Venetoclax should be administered to patients with severe renal impairment (CrCl ≥15 ml/min and <30 ml/min) or end-stage renal disease (ESRD) requiring dialysis (CrCL <15 ml/min) only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS (see section 4.4).

No dose adjustment is needed for patients with mild, moderate, severe renal impairment or end-stage renal disease requiring dialysis (see section 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with mild or moderate, hepatic impairment. Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity at initiation and during the dose-titration phase (see section 4.8).

A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment (see section 5.2). These patients should be monitored more closely for signs of toxicity (see section 4.8).

Paediatric population

The safety and efficacy of venetoclax in children aged less than 18 years have not been established.
Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Venclyxto 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 (see section 5.2). The tablets should not be chewed, crushed, or broken before swallowing.

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

Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax (see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In patients with CLL, concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase (see sections 4.2 and 4.5).

In all patients, concomitant use of preparations containing St. John’s wort (see sections 4.4 and 4.5).

Summary of safety profile

Chronic lymphocytic leukaemia

The overall safety profile of Venclyxto is based on data from 1187 patients with CLL treated in clinical studies with venetoclax in combination with obinutuzumab, ibrutinib, or rituximab, or as monotherapy. The safety analysis included patients from three phase 3 studies (CLL14, GLOW, and MURANO), three phase 2 studies (CAPTIVATE, M13-982, and M14-032), and one phase 1 study (M12-175). CLL14 was a randomised, controlled study in which 212 patients with previously untreated CLL and comorbidities received venetoclax in combination with obinutuzumab. GLOW was an open-label randomised study in which 106 patients with previously untreated CLL received venetoclax in combination with ibrutinib. MURANO was a randomised, controlled study in which 194 patients with previously treated CLL received venetoclax in combination with rituximab.
CAPTIVATE was a multicentre, 2-cohort study in which 323 patients with previously untreated CLL received venetoclax in combination with ibrutinib. In the M13-982, M14-032 and M12-175 studies, 352 patients with previously treated CLL, which included 212 patients with 17p deletion and 146 patients who had failed a B-cell receptor pathway inhibitor were treated with venetoclax monotherapy (see section 5.1).

The most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab, ibrutinib, or rituximab were diarrhoea, neutropenia, nausea, upper respiratory tract infection, fatigue and vomiting. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax in combination with obinutuzumab, ibrutinib, or rituximab were pneumonia, febrile neutropenia, sepsis, neutropenia, anaemia, diarrhoea and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and febrile neutropenia.

The safety of venetoclax in combination with acalabrutinib with or without obinutuzumab was assessed in AMPLIFY, a randomised, controlled study of 575 patients with previously untreated CLL without del (17p) or TP53 mutation. Of the 291 patients treated with venetoclax in combination with acalabrutinib, the most commonly occurring reactions (≥20%) of any grade were infections, neutropenia, headache, bruising, diarrhoea and musculoskeletal pain. The most commonly reported Grade ≥3 adverse reaction (≥5%) was neutropenia. Of the 284 patients treated with venetoclax in combination with acalabrutinib and obinutuzumab, the most commonly occurring adverse reactions of any grade (≥20%) were infections, neutropenia, headache, bruising, diarrhoea, nausea and musculoskeletal pain. The most commonly reported Grade ≥3 adverse reactions (≥5%) were neutropenia and thrombocytopenia.

Acute myeloid leukaemia

The overall safety profile of Venclyxto is based on data from 314 patients with newly diagnosed acute myeloid leukaemia (AML) treated in clinical studies with venetoclax in combination with a hypomethylating agent (azacitidine or decitabine) (VIALE-A phase 3 randomised, and M14-358 phase 1 non-randomised).

In the VIALE-A study, the most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in combination with azacitidine were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage.
In the M14-358 study, the most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in combination with decitabine were thrombocytopenia, febrile neutropenia, nausea, haemorrhage, pneumonia, diarrhoea, fatigue, dizziness/syncope, vomiting, neutropenia, hypotension, hypokalaemia, decreased appetite, headache, abdominal pain, and anaemia.
The most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

The 30-day mortality rate in the VIALE-A study was 7.4% (21/283) with venetoclax in combination with azacitidine and 6.3% (9/144) in the placebo with azacitidine arm.

The 30-day mortality rate in the M14-358 study with venetoclax in combination with decitabine was 6.5% (2/31).

Tabulated list of adverse reactions
Adverse reactions are listed below by MedDRA body system organ class and by frequency.
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Chronic lymphocytic leukaemia

The frequencies of adverse reactions reported with Venclyxto, in combination with obinutuzumab, ibrutinib, or rituximab, or as monotherapy in patients with CLL are summarised in Table 8.

Table 8: Adverse drug reactions reported in patients with CLL treated with venetoclax

System organ class
Frequency
All gradesa
Grade ≥3a
Infections and infestations
Very common
Pneumonia
Upper respiratory tract infection
Urinary tract infection

Common
Sepsis

Sepsis
Pneumonia
Urinary tract infection
Upper respiratory tract infection
Blood and lymphatic system disorders
Very common
Neutropenia
Anaemia
Lymphopenia
Neutropenia
Anaemia
Common
Febrile neutropenia
Febrile neutropenia
Lymphopenia
Metabolism and nutrition disorders

Very common
Hyperkalaemia
Hyperphosphataemia
Hypocalcaemia

Common
Tumour lysis syndrome
Hyperuricaemia

Tumour lysis syndrome
Hyperkalaemia
Hyperphosphataemia
Hypocalcaemia
Hyperuricaemia
Gastrointestinal disorders
Very common
Diarrhoea
Vomiting
Nausea
Constipation
Diarrhoea

Common

Vomiting
Nausea
Uncommon

Constipation
General disorders and administration site conditions

Very common
Fatigue

Common

Fatigue
Investigations

Common
Blood creatinine increased

Uncommon

Blood creatinine increased aOnly the highest frequency observed in the studies is reported (based on studies CLL14, GLOW, CAPTIVATE, MURANO, M13-982, M14-032, and M12-175).

AMPLIFY
When venetoclax is administered in combination with acalabrutinib with or without obinutuzumab, refer to the acalabrutinib SmPC for a description of adverse reactions prior to initiation of treatment.

Acute myeloid leukaemia

The frequencies of adverse reactions reported with Venclyxto in combination with a hypomethylating agent in patients with AML are summarised in Table 9.

Table 9: Adverse drug reactions reported in patients with AML treated with venetoclax

System organ class
Frequency
All gradesa
Grade ≥3a
Infections and infestations
Very common
Pneumoniab
Sepsisb
Urinary tract infection
Pneumoniab
Sepsisb

Common

Urinary tract infection
Blood and lymphatic system disorders
Very common
Neutropeniab
Febrile neutropenia
Anaemiab
Thrombocytopeniab
Neutropeniab
Febrile neutropenia
Anaemiab
Thrombocytopeniab
Metabolism and nutrition disorders

Very common
Hypokalaemia
Decreased appetite
Hypokalaemia
Common
Tumour lysis syndrome
Decreased appetite
Uncommon

Tumour lysis syndrome
Nervous System
Disorders
Very common
Dizziness/syncopeb
Headache

Common

Dizziness/syncopeb
Uncommon

Headache
Vascular Disorders
Very common
Hypotension
Haemorrhageb
Haemorrhageb
Common

Hypotension
Respiratory, thoracic, and mediastinal disorder
Very common
Dyspnoea

Common

Dyspnoea
Gastrointestinal disorders
Very common
Nausea
Diarrhoea
Vomiting
Stomatitis
Abdominal pain

Common

Nausea
Diarrhoea
Vomiting
Uncommon

Stomatitis
Hepatobiliary
Disorders
Common
Cholecystitis/cholelithiasisb
Cholecystitis/cholelithiasisb
Musculoskeletal disorders and connective tissue disorders
Very common
Arthralgia

Uncommon

Arthralgia
General disorders and administration site conditions

Very common
Fatigue
Asthenia

Common

Fatigue
Asthenia

Investigations

Very common
Weight decreased
Blood bilirubin increased

Common

Weight decreased
Blood bilirubin increased aOnly the highest frequency observed in the studies is reported (based on studies VIALE-A and M14-358).
bIncludes multiple adverse reaction terms.

Discontinuation and dose reductions due to adverse reactions

Chronic lymphocytic leukaemia

Discontinuations due to adverse reactions in the AMPLIFY study occurred in 8% of patients treated with venetoclax in combination with acalabrutinib, and in 20% of patients treated with venetoclax in combination with acalabrutinib and obinutuzumab.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and MURANO studies, and in 21% and 7% of patients treated with venetoclax in combination with ibrutinib in the GLOW and CAPTIVATE studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions in the AMPLIFY study occurred in 14% of patients treated with venetoclax in combination with acalabrutinib, and in 21% of patients treated with venetoclax in combination with acalabrutinib and obinutuzumab.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with venetoclax in combination with obinutuzumab in the CLL14 study, in 26% and 20% of patients treated with venetoclax in combination with ibrutinib in the GLOW and CAPTIVATE studies, respectively, in 15% of patients treated with venetoclax in combination with rituximab in the MURANO study, and in 14% of patients treated with venetoclax in the monotherapy studies.

Dose interruptions due to adverse reactions in the AMPLIFY study occurred in 50% of patients treated with venetoclax in combination with acalabrutinib, and in 65% of patients treated with venetoclax in combination with acalabrutinib and obinutuzumab. The most common adverse reaction that led to dose interruption of venetoclax in the AMPLIFY study was neutropenia (33% and 26% with or without obinutuzumab, respectively).

Dose interruptions due to adverse reactions occurred in 74% of patients treated with the combination of venetoclax and obinutuzumab in the CLL14 study, in 67% of patients treated with the combination of venetoclax and ibrutinib in the GLOW study, and in 71% of patients treated with the combination of venetoclax and rituximab in the MURANO study; the most common adverse reaction that led to dose interruption of venetoclax was neutropenia (41%, 19%, and 43% in the CLL14, GLOW, and MURANO studies, respectively). In the monotherapy studies with venetoclax, dose interruptions due to adverse reactions occurred in 40% of patients; the most common adverse reaction leading to dose interruption was neutropenia (5%).

Acute myeloid leukaemia

In the VIALE-A study, discontinuations of venetoclax due to adverse reactions occurred in 24% of patients treated with the combination of venetoclax and azacitidine. Venetoclax dosage reductions due to adverse reactions occurred in 2% of patients. Venetoclax dose interruptions due to adverse reactions occurred in 72% of patients. Among patients who achieved bone marrow clearance of leukaemia, 53% underwent dose interruptions for ANC <500/microlitre. The most common adverse reaction that led to dose interruption (>10%) of venetoclax were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia.

In the M14-358 study, discontinuations due to adverse reactions occurred in 26% of patients treated with the combination of venetoclax and decitabine. Dosage reductions due to adverse reactions occurred in 6% of patients. Dose interruptions due to adverse reactions occurred in 65% of patients;
the most common adverse reactions that led to dose interruption (≥5%) of venetoclax were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Description of selected adverse reactions

Tumour lysis syndrome

Tumour lysis syndrome is an important identified risk when initiating venetoclax.

Chronic lymphocytic leukaemia

In the initial Phase 1 dose-finding studies, which had a shorter (2 to 3 week) titration phase and higher starting dose, 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.

The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures. In venetoclax clinical studies, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 109/l and any measurable lymph node ≥5 cm were hospitalised to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the titration phase (see section 4.2).

In 168 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg in studies M13-982 and M14-032, the rate of TLS was 2%. All events were laboratory TLS (laboratory abnormalities that met ≥2 of the following criteria 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) and occurred in patients who had a lymph node(s) ≥5 cm or ALC ≥25 x 109/l. 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 CrCl ≥50 ml/min.

In the open-label, randomised phase 3 study (MURANO), the incidence of TLS was 3% (6/194) in patients treated with venetoclax + rituximab. After 77/389 patients were enrolled in the study, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in “Posology” (see section 4.2). All events of TLS occurred during the venetoclax dose-titration phase and resolved within two days. All six patients completed the dose-titration and reached the recommended daily dose of 400 mg of venetoclax. No clinical TLS was observed in patients who followed the current 5-week dose-titration schedule and TLS prophylaxis and monitoring measures (see section 4.2). The rates of grade ≥3 laboratory abnormalities relevant to TLS were hyperkalaemia 1%, hyperphosphataemia 1%, and hyperuricaemia 1%.

In the open-label, randomised phase 3 study (CLL14), the incidence of TLS was 1.4% (3/212) in patients treated with venetoclax + obinutuzumab. All three events of TLS resolved and did not lead to withdrawal from the study. Obinutuzumab administration was delayed in two cases in response to the TLS events.

In the open-label, randomised phase 3 study (AMPLIFY), the incidence of TLS was 0.3% (1/291) in patients treated with venetoclax + acalabrutinib, and 0.4% (1/284) in patients treated with venetoclax + acalabrutinib + obinutuzumab. Obinutuzumab administration was delayed in response to the TLS event. Both cases were laboratory TLS that resolved and did not lead to withdrawal from the study.

No adverse event of TLS was observed in the randomised phase 3 GLOW study.

The incidence of laboratory TLS was 0.3% (1/323) in the single-arm phase 2 CAPTIVATE study, reported in one patient in the MRD-guided cohort.

During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax (see sections 4.2 and 4.4).

Acute myeloid leukaemia

In the randomised, phase 3 study (VIALE-A) with venetoclax in combination with azacitidine the incidence of TLS was 1.1% (3/283, 1 clinical TLS). The study required reduction of white blood cell count to <25 x 109/l prior to venetoclax initiation and a dose-titration schedule in addition to standard prophylaxis and monitoring measures (see section 4.2). All cases of TLS occurred during dose-titration.

In M14-358 study, no events of laboratory or clinical TLS were reported with venetoclax in combination with decitabine.

Neutropenia and infections

Neutropenia is an identified risk with Venclyxto treatment.

Chronic lymphocytic leukaemia

In the AMPLIFY study, neutropenia/neutrophil count decreased/febrile neutropenia (all grades) was reported in 37% of patients in the venetoclax + acalabrutinib arm. Dose interruption occurred in 26% of patients and 0.7% of patients discontinued venetoclax due to neutropenia/neutrophil count decreased/febrile neutropenia. Grade ≥3 neutropenia/neutrophil count decreased/febrile neutropenia was reported in 32% of patients. Grade ≥3 infections were reported in 12% and serious infections in 12% of patients. Fatal infections occurred in 3.1% of patients (most frequently reported COVID-19 or COVID-19 pneumonia).

In the AMPLIFY study, neutropenia/neutrophil count decreased/febrile neutropenia (all grades) was reported in 50% of patients in the venetoclax + acalabrutinib + obinutuzumab arm. Dose interruption occurred in 33% of patients and 1% of patients discontinued venetoclax due to neutropenia/neutrophil count decreased/febrile neutropenia. Grade ≥3 neutropenia/neutrophil count decreased/febrile neutropenia was reported in 46% of patients. Grade ≥3 infections were reported in 24% and serious infections in 24% of patients. Fatal infections occurred in 6% of patients (most frequently reported COVID-19 or COVID-19 pneumonia).

In the CLL14 study, neutropenia (all grades) was reported in 58% of patients in the venetoclax + obinutuzumab arm; 41% of patients treated with venetoclax + obinutuzumab experienced dose interruption and 2% of patients discontinued venetoclax due to neutropenia. Grade 3 neutropenia was reported in 25% of patients and grade 4 neutropenia in 28% of patients. The median duration of grade 3 or 4 neutropenia was 22 days (range: 2 to 363 days). Febrile neutropenia was reported in 6% of patients, grade ≥3 infections in 19%, and serious infections in 19% of patients. Deaths due to infection occurred in 1.9% of patients while on treatment and 1.9% of patients following treatment discontinuation.

In the venetoclax + ibrutinib arm in the GLOW study, all-grade neutropenia/neutrophil count decreased was reported in 42% of patients, including grade 3 or 4 events in 35% of patients. Nineteen percent experienced dose interruption and 8% had dose reduction of venetoclax due to neutropenia/neutrophil count decreased. In the venetoclax + ibrutinib arm versus the obinutuzumab + chlorambucil arm, respectively, the following were reported: febrile neutropenia 2% versus 3%, grade ≥3 infections 17% versus 11%, and serious infections 12% versus 9%.

In the CAPTIVATE study, all-grade neutropenia/neutrophil count decreased was reported in 47% of patients in the venetoclax + ibrutinib arm, including grade 3 or 4 events in 37% of patients. Fourteen

percent experienced dose interruption, 4% had dose reduction and 1 patient (0.3%) discontinued venetoclax due to neutropenia/neutrophil count decreased. Febrile neutropenia was reported in 1%, grade ≥3 infections in 8%, and serious infections in 8% of patients.

In the MURANO study, neutropenia (all grades) was reported in 61% of patients in the venetoclax + rituximab arm. Forty-three percent of patients treated with venetoclax + rituximab experienced dose interruption and 3% of patients discontinued venetoclax due to neutropenia. Grade 3 neutropenia was reported in 32% of patients and grade 4 neutropenia in 26% of patients. The median duration of grade 3 or 4 neutropenia was 8 days (range: 1 to 712 days). With venetoclax + rituximab treatment, febrile neutropenia was reported in 4% of patients, grade ≥3 infections in 18%, and serious infections in 21% of patients.

Acute myeloid leukaemia

In the VIALE-A study, grade ≥3 neutropenia was reported in 45% of patients. The following were also reported in the venetoclax + azacitidine arm versus the placebo + azacitidine arm, respectively: febrile neutropenia 42% versus 19%, grade ≥3 infections 64% versus 51%, and serious infections 57% versus 44%.

In the M14-358 study, neutropenia was reported in 35% (all grades) and 35% (grade 3 or 4) of patients in the venetoclax + decitabine arm.

Paediatric population
The safety profile of venetoclax in paediatric patients is based on data from an open-label phase 1 study (M13-833) in 140 paediatric and young adult patients with relapsed or refractory malignancies (see section 5.1). No new risks or safety concerns were identified in the study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Tumour lysis syndrome

Tumour lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax (see section 4.8).

Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS at initiation and during the 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.
During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax. Information described in section 4.2, including risk assessment, prophylactic measures, dose-titration and modification schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.

The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden, and splenomegaly in CLL.

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. More intensive measures (intravenous hydration, frequent monitoring, hospitalisation) should be employed as overall risk increases. Dosing should be interrupted if needed;
when restarting venetoclax, dose modification guidance should be followed (see Table 4 and Table 5).
The instructions for “Prevention of tumour lysis syndrome (TLS)” should be followed (see section 4.2).

Concomitant use of this medicinal product with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation and during the dose-titration phase (see sections 4.2 and 4.3). Also, inhibitors of P-gp or BCRP may increase venetoclax exposure (see section 4.5).

Neutropenia and infections

In patients with CLL, grade 3 or 4 neutropenia has been reported in patients treated with venetoclax in combination studies and in monotherapy studies (see section 4.8).

In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. The neutrophil counts can worsen with venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy.

Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia (see section 4.2).

Serious infections, including sepsis with fatal outcome, have been reported (see section 4.8).
Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials, dose interruption or reduction, and use of growth factors (e.g., G-CSF) as appropriate (see section 4.2).

Immunisation

The safety and efficacy of immunisation with live attenuated vaccines during or following venetoclax therapy have not been studied. Live vaccines should not be administered during treatment and thereafter until B-cell recovery.

CYP3A inducers

Co-administration of CYP3A4 inducers may lead to decreased venetoclax exposure and consequently a risk for lack of efficacy. Concomitant use of venetoclax with strong or moderate CYP3A4 inducers should be avoided (see sections 4.3 and 4.5).

Women of childbearing potential

Women of childbearing potential must use a highly effective method of contraception while taking venetoclax (see section 4.6).

Excipients with known effect

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.

Venetoclax is predominantly metabolised by CYP3A.

Agents that may alter venetoclax plasma concentrations

CYP3A inhibitors

Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days in 11 patients increased venetoclax Cmax to 2.3-fold and AUC to 6.4-fold. Co-administration of 50 mg once daily ritonavir, a strong CYP3A and P-gp inhibitor, for 14 days in 6 healthy subjects increased venetoclax Cmax to 2.4-fold and AUC by 7.9-fold. Compared with venetoclax 400 mg administered alone, co-administration of 300 mg posaconazole, a strong CYP3A and P-gp inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients increased venetoclax Cmax to 1.6-fold and 1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively. Co-administration of venetoclax with other strong CYP3A4 inhibitors is predicted to increase venetoclax AUC by on average 5.8- to 7.8-fold.

For patients requiring concomitant use of venetoclax with strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil), venetoclax dosing should be administered according to Table 7. 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 to 3 days after discontinuation of the inhibitor (see section 4.2).

Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A.

P-gp and BCRP inhibitors

Venetoclax is a substrate for P-gp and BCRP. Co-administration of a 600 mg single dose of rifampicin, a P-gp inhibitor, in 11 healthy subjects increased venetoclax Cmax by 106% and AUC by 78%. Concomitant use of venetoclax with P-gp and BCRP inhibitors at initiation and during the dose-titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of toxicities (see section 4.4).

Ibrutinib

In studies of ibrutinib (420 mg) in combination with venetoclax (400 mg) in CLL patients, an increase in venetoclax exposure (approximately 1.8-fold based on AUC) was observed compared with monotherapy data for venetoclax.

CYP3A inducers

Co-administration of 600 mg once daily rifampicin, a strong CYP3A inducer, for 13 days in 10 healthy subjects decreased venetoclax Cmax by 42% and AUC by 71%. Concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampicin) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. Alternative

treatments with less CYP3A induction should be considered. Preparations containing St. John's wort are contraindicated during treatment with venetoclax, as efficacy may be reduced (see section 4.3).

Azithromycin

In a drug-drug interaction study in 12 healthy subjects, co-administration of 500 mg of azithromycin on the first day followed by 250 mg of azithromycin once daily for 4 days decreased venetoclax Cmax by 25% and AUC by 35%. No dose adjustment is needed during short-term use of azithromycin when administered concomitantly with venetoclax.

Gastric acid reducing agents

Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect venetoclax bioavailability.

Bile acid sequestrants

Co-administration of bile acid sequestrants with venetoclax is not recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with venetoclax, the SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and venetoclax should be administered at least 4-6 hours after the sequestrant.

Agents that may have their plasma concentrations altered by venetoclax

Warfarin

In a drug-drug interaction study in three healthy volunteers, administration of a single dose of 400 mg venetoclax with 5 mg warfarin resulted in an 18% to 28% increase in Cmax and AUC of R-warfarin and S-warfarin. Because venetoclax was not dosed to steady state, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving warfarin.

Substrates of P-gp, BCRP, and OATP1B1

Venetoclax is a P-gp, BCRP and OATP1B1 inhibitor in vitro. In a drug-drug interaction study, administration of a single 100 mg dose of venetoclax with 0.5 mg digoxin, a P-gp substrate, resulted in a 35% increase in digoxin Cmax and a 9% increase in digoxin AUC. Co-administration of narrow therapeutic index P-gp, or BCRP substrates (e.g., digoxin, dabigatran, everolimus, sirolimus) with venetoclax should be avoided.

If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with caution.
For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract (e.g., dabigatran etexilate), its administration should be separated from venetoclax administration as much as possible to minimise a potential interaction.

If a statin (OATP substrate) is used concomitantly with venetoclax, close monitoring of statin-related toxicity is recommended.

Women of childbearing potential/Contraception in females

Women should avoid becoming pregnant while taking Venclyxto 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.

Pregnancy

Based on embryo-foetal toxicity studies in animals (see section 5.3), 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 (see section 5.3). Venetoclax is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception.

Breast-feeding

It is unknown whether venetoclax or its metabolites are excreted in human milk.

A risk to the breast-feeding child cannot be excluded.

Breast-feeding should be discontinued during treatment with Venclyxto.

Fertility

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 (see section 5.3). Before starting treatment, counselling on sperm storage may be considered in some male patients.

Venclyxto has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients taking venetoclax and should be considered when assessing a patient’s ability to drive or operate machines.

There is no specific antidote for venetoclax. Patients who experience overdose should be closely monitored and appropriate supportive treatment provided. During dose-titration phase, treatment should be interrupted, and patients should be monitored carefully for signs and symptoms of TLS (fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle or joint pain, abdominal pain, and distension) along with other toxicities (see section 4.2). Dialysis does not result in removal of venetoclax.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX52

Mechanism of action

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 and AML 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.

Pharmacodynamic effects

Cardiac electrophysiology

The effect of multiple doses of venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an open-label, single-arm study in 176 patients. Venetoclax had no effect on QTc interval and there was no relationship between venetoclax exposure and change in QTc interval.

Clinical efficacy and safety

Chronic lymphocytic leukaemia

Venetoclax in combination with acalabrutinib with or without obinutuzumab for the treatment of patients with previously untreated CLL – study ACE-CL-311 (AMPLIFY)

A randomised (1:1:1), multi-centre, open-label Phase 3 study of 867 patients evaluated the safety and efficacy of venetoclax + acalabrutinib versus venetoclax + acalabrutinib + obinutuzumab versus Investigator’s choice of chemoimmunotherapy, either FCR (fludarabine plus cyclophosphamide plus rituximab) or BR (bendamustine plus rituximab) in patients with previously untreated CLL.
AMPLIFY included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. The trial allowed patients to receive antithrombotic agents except warfarin and other vitamin K antagonists.

Patients were randomised in a 1:1:1 ratio into 3 arms to receive:

• Venetoclax + acalabrutinib: Acalabrutinib 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle 3 Day 1, patients started the venetoclax 5-week dose-titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily.
Venetoclax was administered for a total of 12 cycles. Each cycle was 28 days.

Absorption

Following multiple oral administrations, maximum plasma concentration of venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg. Under low-fat meal conditions, venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 mcg /ml and AUC24 was 32.8 ± 16.9 mcg •h/ml at the 400 mg once daily dose.

Effect of food

Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions. It is recommended that venetoclax should be administered with a meal (see section 4.2).

Distribution

Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/ml). The mean blood-to-plasma ratio was 0.57.
The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients.

Biotransformation

In vitro studies demonstrated that venetoclax is predominantly metabolised by cytochrome P450 CYP3A4. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro.

In vitro interaction studies

Co-administration with CYP and UGT substrates

In vitro studies indicated that venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9 and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7.

Co-administration with transporter substrates/inhibitors