4.1. Therapeutic indications

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 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.

4.2. Posology and method of administration

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

1

20 mg

2

50 mg

3

100 mg

4

200 mg

5

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

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 increase schedule (see Table 1). After completing the dose increase schedule, patients should continue venetoclax 400 mg once daily in combination with ibrutinib 420 mg orally once daily to the end of Cycle 15.

Refer to the ibrutinib prescribing information 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 dose of venetoclax depends upon the combination agent.

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

1

100 mg

2

200 mg

3

400 mg

4 and beyond

400 mg

when dosing in combination with a hypomethylating agent

600 mg

when dosing in combination with low-dose cytarabine

A hypomethylating agent (azacitidine or decitabine) or low‑dose cytarabine should be initiated on Cycle 1 Day 1.

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.

or

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.

or

Cytarabine should be administered at a dose of 20 mg/m2 subcutaneously once daily on Days 1‑10 of each 28‑day cycle beginning on Cycle 1 Day 1.

Refer to the azacitidine or decitabine or low‑dose cytarabine prescribing information for additional information.

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

Venetoclax, in combination with a hypomethylating agent (azacitidine or decitabine) or low‑dose cytarabine, 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.

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)

400

300

300

200

200

100

100

50

50

20

20

10

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 or 4 days with low‑dose cytarabine (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 or low dose cytarabine 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 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 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 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 or low dose cytarabine, 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.

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).

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 or low dose cytarabine. 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”.

4.5. Interaction with other medicinal products and other forms of interaction

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).

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of safety profile

Chronic lymphocytic leukaemia

The overall safety profile of Venclyxto is based on data from 758 patients with CLL treated in clinical studies with venetoclax in combination with obinutuzumab or rituximab or as monotherapy. The safety analysis included patients from two phase 3 studies (CLL14 and MURANO), two phase 2 studies (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. MURANO was a randomised, controlled study in which 194 patients with previously treated CLL received venetoclax in combination with rituximab. In the phase 2 and phase 1 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 or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. 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 or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and febrile neutropenia.

AMPLIFY was a randomised, controlled study in which 575 patients with previously untreated CLL without del(17p) or TP53 mutation received venetoclax in combination with acalabrutinib with or without obinutuzumab. For a description of adverse reactions in patients receiving venetoclax in combination with acalabrutinib with or without obinutuzumab, refer to the acalabrutinib SmPC.

GLOW (CLL3011)

GLOW was an open-label randomized (1:1) phase 3 study in patients with previously untreated CLL/SLL who were 65 years or older, or patients <65 years of age with a Cumulative Illness Rating Scale (CIRS) score >6 or CrCL <70 mL/min. Patients received 3 cycles of single‑agent ibrutinib (420 mg/day orally). Starting at Cycle 4, venetoclax was added (starting with the 5‑week dose-titration to the recommended daily dose of 400 mg) to the ibrutinib regimen continuously for 12 additional cycles.

At the time of primary data analysis (26 February 2021), the median duration of exposure was 13.8 months in the venetoclax + ibrutinib arm and 5.13 months in the chlorambucil + obinutuzumab arm.

In the venetoclax + ibrutinib arm, adverse events led to discontinuation of venetoclax in 11% of patients, dose reductions in 17% of patients, and dose interruptions in 42% of patients. The most common adverse reaction that led to dose interruption of venetoclax was neutropenia.

CAPTIVATE (PCYC-1142-CA)

The safety of venetoclax in combination with ibrutinib was evaluated in a multi‑center, 2‑cohort study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration (FD) therapy in adult patients who were 70 years or younger with previously untreated CLL or SLL. Patients in both cohorts received 3 cycles of single‑agent ibrutinib (420 mg/day orally). Starting at Cycle 4, venetoclax was added (starting with the 5‑week dose titration to the recommended daily dose of 400 mg) to the ibrutinib regimen continuously for at least 12 additional cycles. Safety was assessed in an all-treated pool consisting of the MRD-guided cohort (first 16 cycles) plus the FD cohort.

At the time of primary data analysis (12 November 2020), the median duration of exposure was 11.5 months for venetoclax and 14.1 months for ibrutinib.

Adverse events led to discontinuation of venetoclax in 3% of patients and dose reductions in 12% of patients.

Acute myeloid leukaemia

The overall safety profile of Venclyxto is based on data from 456 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) or low dose cytarabine (VIALE C phase 3 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 VIALE-C study, the most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in the combination with low dose cytarabine were neutropenia, thrombocytopenia, nausea, febrile neutropenia, anaemia, vomiting, diarrhoea, hypokalaemia, decreased appetite and pneumonia. The most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia and sepsis.

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 VIALE‑C study was 12.7% (18/142) with venetoclax in combination with low-dose cytarabine and 16.2% (11/68) in the placebo with low‑dose cytarabine 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, 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

Common

Sepsis

Urinary tract infection

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

Common

Diarrhoea

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, MURANO, M13-982, M14-032, and M12-175).

AMPLIFY

When venetoclax is administered in combination with acalabrutinib, refer to the SmPC for acalabrutinib prior to initiation of treatment.

The adverse reactions observed with venetoclax in combination with acalabrutinib, with or without obinutuzumab, were consistent with those reported for each individual component of the respective combination regimens (see Table 8 and acalabrutinib SmPC).

Table 9 provides the adverse reactions reported in study CLL3011(GLOW). Adverse reactions are listed by MedDRA body system organ class, rate, and frequency.

Table 9: Summary of Adverse Reactions Reported with Incidence of ≥10% and ≥5% Higher for all Grades or ≥2% Higher for Grade 3 or 4 in Patients Treated with Venetoclax Plus Ibrutinib Compared with Obinutuzumab Plus Chlorambucil in GLOW

Adverse Reaction by Body System

Venetoclax + Ibrutinib

(N = 106)

Obinutuzumab + Chlorambucil

(N = 105)

All Grades

%

(Frequency)

Grade 3 or 4

%

All Grades

%

Grade 3 or 4

%

Gastrointestinal disorders

Diarrhea

51

(Very common)

10

12

<1

General disorders and administration site conditions

Fatigue

15

(Very common)

<1

10

0

Infections & infestations

Urinary tract infection

16

(Very common)

2

5

2

Pneumoniab

13

(Very common)

7

10

5

Metabolism and nutrition disorders:

Hyperphosphatemia

10

(Very common)

<1

<1

0

aIncludes pneumonia, bronchopulmonary aspergillosis, lung abscess, pneumonia cytomegaloviral, and pneumonia streptococcal.

Other adverse reactions reported in the venetoclax + ibrutinib arm are presented below:

Blood & lymphatic system disorders: neutropeniaa (42%), anemia (18%), febrile neutropenia (2%), lymphocyte count decreased (<1%)

Gastrointestinal Disorders: nausea (26%), vomiting (14%), constipation (10%)

Infections & infestations: upper respiratory tract infection (12%), sepsisb (<1%)

Investigations: blood creatinine increased (5%)

Metabolism and nutrition disorders: hyperkalemiac (9%), hyperuricemiad (7%), hypocalcemiae (4%)

aneutropenia and neutrophil count decreased.

bIncludes septic shock.

cIncludes hyperkalemia and blood potassium increased.

dIncludes hyperuricemia and blood uric acid increased.

eIncludes hypocalcemia and blood calcium decreased.

Table 10 provides the adverse reactions reported in 10% or more of patients in study PCYC-1142-CA (CAPTIVATE), listed by MedDRA body system organ class and rate.

Table 10: Summary of Adverse Reactions Reported with Incidence of ≥10% (all grade) in Patients Treated with Venetoclax Plus Ibrutinib in the FD and MRD (First 16 Cycles) Cohorts in CAPTIVATE

Adverse Reaction by Body System

Venetoclax + Ibrutinib

N = 323

All grades

%

Grade 3 or 4

%

Gastrointestinal disorders

Diarrhea

67

4

Nausea

44

<1

Vomiting

22

1

Constipation

16

0

Blood & lymphatic system disorders

Neutropeniaa

47

37

General disorders and administration site conditions

Fatigue

26

2

Infections and infestations

Upper respiratory tract infection

26

0

aIncludes neutropenia and neutrophil count decreased.

Other adverse reactions reported in the CAPTIVATE study are presented below:

Blood & lymphatic system disorders: anemia (7%), febrile neutropenia (1%), lymphopeniaa (<1%)

Infections & infestations: urinary tract infection (7%), pneumoniab (4%), sepsisc (1%)

Investigations: blood creatinine increased (6%)

Metabolism and nutrition disorders: hyperphosphatemiad (7%), hyperuricemiae (7%), hyperkalemiaf (6%), hypocalcemiag (3%), tumor lysis syndrome (<1%; 1 patient in MRD [first 16 cycles] cohort)

aIncludes lymphopenia and lymphocyte count decreased.

bIncludes pneumonia, pleurisy viral, pneumonia bacterial.

cIncludes bacteremia, disseminated varicella zoster virus infection, Escherichia bacteremia, staphylococcal bacteremia.

dIncludes hyperphosphatemia and blood phosphorus increased.

eIncludes hyperuricemia and blood uric acid increased.

fIncludes hyperkalemia and blood potassium increased.

gIncludes hypocalcemia and blood calcium decreased.

Acute myeloid leukaemia

The frequencies of adverse reactions reported with Venclyxto in combination with a hypomethylating agent or low dose cytarabine in patients with AML are summarised in Table 11.

Table 11: 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

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, VIALE C 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 20% and 8% of patients treated with venetoclax in combination with acalabrutinib with or without obinutuzumab, respectively. 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, 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 21% and 14% of patients treated with venetoclax in combination with acalabrutinib with or without obinutuzumab, respectively. Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in the CLL14 study, in 15% of patients treated with the combination of venetoclax and 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 65% and 50% of patients treated with venetoclax in combination with acalabrutinib with or without obinutuzumab, respectively. 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 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% and 43% in the CLL14 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

Venetoclax in combination with a hypomethylating agent

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.

Venetoclax in combination with low-dose cytarabine in randomised study (VIALE‑C)

In the VIALE‑C study, discontinuations of venetoclax due to adverse reactions occurred in 26% of patients treated with the combination of venetoclax and low-dose cytarabine. Venetoclax dosage reductions due to adverse reactions occurred in 10% of patients. Venetoclax dose interruptions due to adverse reactions occurred in 63% of patients. Among patients who achieved bone marrow clearance of leukaemia, 37% underwent dose interruptions for ANC <500/μL. The most common adverse reactions that led to dose interruption (>5%) of venetoclax were neutropenia, thrombocytopenia, pneumonia febrile neutropenia, and anaemia.

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 randomized 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) and in the phase 3 study (VIALE‑C) with venetoclax in combination with low dose cytarabine the incidence of TLS was 5.6% (8/142, 4 clinical TLS, 2 of which were fatal). The studies 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.

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.

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 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.

In the venetoclax + ibrutinib arm in the GLOW study, neutropenia (all grades) was reported in 42% of patients; grade 3 or 4 neutropenia was reported in 35% of patients. Nineteen percent experienced dose interruption and 8% had dose reduction due to neutropenia. In the venetoclax + ibrutinib arm versus the obinutuzumab + chlorambucil arm, respectively, the following were reported: febrile neutropenia 2% versus 3%, grade ≥3 infections 7% versus 9%, and serious infections 12% versus 9%.

In the CAPTIVATE study, neutropenia (all grades) was reported in 47% of patients in the venetoclax + ibrutinib arm; grade 3 or 4 neutropenia was reported in 37% of patients. Fourteen percent experienced dose interruption, 4% had dose reduction and 1 patient (0.3%) discontinued venetoclax due to neutropenia. Febrile neutropenia was reported in 1%, grade ≥3 infections in 8%, and serious infections in 8% 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.

In the VIALE‑C study, grade ≥3 neutropenia was reported in 53% of patients. The following were also reported in the venetoclax + low-dose cytarabine arm versus the placebo + low-dose cytarabine arm, respectively: febrile neutropenia 32% versus 29%, grade ≥3 infections 43% versus 50%, and serious infections 37% versus 37%.

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 Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.