VENCLYXTO 50 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Venclyxto 50 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

3   PHARMACEUTICAL FORM

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).

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

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

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.

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

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 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 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. Assess patient-specific factors for level of TLS risk and provide prophylactic hydration and anti-hyperuricaemics 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 trial 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

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

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

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 dosetitration 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 × 109/1 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

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

aIn patients with CLL, avoid concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during the dose-titration phase. Consider alternative medications 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” above). Venetoclax should be administered to patients with severe renal impairment (CrCl >15 ml/min and <30 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 or severe renal impairment (CrCl >15 ml/min and <90 ml/min) (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. No data are available.

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” 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 with rituximab or obinutuzumab 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).

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. Coadministration 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 rifampin, 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 rifampin, 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, rifampin) 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 séquestrants

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 coadministered 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 trials 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 trial in which 212 patients with previously untreated CLL and comorbidities received venetoclax in combination with obinutuzumab. MURANO was a randomised, controlled trial 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.

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 trials 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

aOnly the highest frequency observed in the trials is reported (based on studies CLL14, MURANO, M13–982, M14–032, and M12–175).

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 9.

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

Discontinuation and dose reductions due to adverse reactions

Chronic Lymphocytic Leukaemia

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 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 14% of patients treated with venetoclax in the monotherapy studies.

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. Dose 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/^L. 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 × 109/1 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 ^mol/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 × 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.

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 × 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 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.

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%.

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). Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 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 obinutuzumab for the treatment of patients with previously untreated CLL – study BO25323 (CLL14)

A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of venetoclax + obinutuzumab versus obinutuzumab + chlorambucil in patients with previously untreated CLL and comorbidities (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance [CrCl] <70 ml/min). Patients in the study were assessed for risk of TLS and received prophylaxis accordingly prior to obinutuzumab administration. All patients received obinutuzumab at 100 mg on Cycle 1 Day 1, followed by 900 mg which could have been administered on Day 1 or Day 2, then 1000 mg doses on Days 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle, for a total of 6 cycles. On Day 22 of Cycle 1, patients in the venetoclax + obinutuzumab arm began the 5-week venetoclax dose-titration schedule, continuing through Cycle 2 Day 28. Upon completion of the dose-titration schedule, patients continued venetoclax 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12. Each cycle was 28 days. Patients randomised to the obinutuzumab + chlorambucil arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1–12. Patients continued to be followed for disease progression and overall survival after completing therapy.

Baseline demographic and disease characteristics were similar between the study arms. The median age was 72 years (range: 41 to 89 years), 89% were white, and 67% were male; 36% and 43% were Binet stage B and C, respectively. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CrCl <70 ml/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 10%, 11q deletion in 19%, and unmutated IgVH in 57%. The median follow-up at the time of the primary analysis was 28 months (range: 0 to 36 months).

At baseline, the median lymphocyte count was 55 × 109 cells/l in both study arms. On Cycle 1 Day 15, the median count had decreased to 1.03 × 109 cells/l (range: 0.2 to 43.4 × 109 cells/l) in the obinutuzumab + chlorambucil arm and 1.27 × 109 cells/l (range: 0.2 to 83.7 × 109 cells/l) in the venetoclax + obinutuzumab arm.

Progression-free survival (PFS) was assessed by investigators and by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).

Efficacy results for investigator-assessed PFS at the time of the primary analysis (data cut-off date 17 August 2018) are shown in Table 10.

Table 10: Investigator-assessed progression-free survival in patients with previously untreated CLL in CLL14 (primary analysis)

At an updated efficacy analysis (data cut-off date 23 August 2019 and median followup of 40 months), the median PFS had not been reached in the venetoclax + obinutuzumab arm and was 35.6 months [95% CI: 33.7, 40.7] in the obinutuzumab + chlorambucil arm with a HR of 0.31 [95% CI: 0.22, 0.44]. The 36-month PFS estimate in the venetoclax + obinutuzumab arm was 82% [95% CI: 76.5, 87.3] and in the obinutuzumab + chlorambucil arm was 50% [95% CI: 42.4, 56.6]. The updated Kaplan-Meier curve for PFS is shown in Figure 1.

Figure 1: Kaplan-Meier curve of investigator-assessed progression-free survival (ITT population) in CLL14 with 40 months follow-up

Table 11: Additional efficacy results in CLL14 (primary analysis)

CR+CRi.

cMinimal residual disease was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cut-off for a negative status was <1 CLL cell per 104 leukocytes.

dPer protocol, MRD in bone marrow was to be assessed only in responding patients (CR/CRi and PR).

The PFS benefit with venetoclax + obinutuzumab versus obinutuzumab + chlorambucil treatment was observed across the following subgroups: sex; age; Binet stage at screening; estimated CrCL; del(17p)/TP53 mutation; IgVH mutational status.

Venetoclax in combination with rituximab for the treatment of patients with CLL who have received at least one prior therapy – study GO28667 (MURANO)

A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of venetoclax + rituximab versus BR in patients with previously treated CLL. Patients in the venetoclax + rituximab arm completed the Venclyxto 5-week dosetitration schedule and then received 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab was initiated after the 5-week dose-titration schedule at 375 mg/m2 for Cycle 1 and 500 mg/m2 for Cycles 2–6. Each cycle was 28 days. Patients randomised to BR received bendamustine at 70 mg/m2 on Days 1 and 2 for 6 cycles and rituximab as described above.

Median age was 65 years (range: 22 to 85); 74% were male, and 97% were white. Median time since diagnosis was 6.7 years (range: 0.3 to 29.5). Median prior lines of therapy was 1 (range: 1 to 5); and included alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%) and prior purine analogs (81%, including 55% FCR). At baseline, 47% of patients had one or more nodes >5 cm, and 68% had ALC >25 × 109/1. A 17p deletion was detected in 27% of patients, TP53 mutations in 26%, 11q deletion in 37%, and unmutated IgVH gene in 68%. Median follow-up time for primary analysis was 23.8 months (range: 0.0 to 37.4 months).

Progression-free survival (PFS) was assessed by investigators using the International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).

At the time of the primary analysis (data cut-off date 8 May 2017), 16% (32/194) of patients in the venetoclax + rituximab arm had experienced a PFS event, compared with 58% (114/195) in the bendamustine + rituximab arm (hazard ratio: 0.17 [95% CI: 0.11, 0.25]; P<0.0001, stratified log-rank test). The PFS events included 21 disease progression and 11 death events in the venetoclax + rituximab arm, and 98 disease progression and 16 death events in the bendamustine + rituximab arm. Median PFS was not reached in the venetoclax + rituximab arm and was 17.0 months [95% CI: 15.5, 21.6] in the bendamustine + rituximab arm.

The 12– and 24-month PFS estimates were 93% [95% CI: 89.1, 96.4] and 85% [95% CI: 79.1, 90.6] in the venetoclax + rituximab arm and 73% [95% CI: 65.9, 79.1] and 36% [95% CI: 28.5, 44.0] in the bendamustine + rituximab arm, respectively.

Efficacy results for the primary analysis were also assessed by an Independent Review Committee (IRC) demonstrating a statistically significant 81% reduction in the risk of progression or death for patients treated with venetoclax + rituximab (hazard ratio: 0.19 [95% CI: 0.13, 0.28]; p<0.0001).

Investigator-assessed ORR for patients treated with venetoclax + rituximab was 93% [95% CI: 88.8, 96.4], with a CR + CRi rate of 27%, nPR rate of 3%, and PR rate of 63%. For patients treated with bendamustine + rituximab, ORR was 68% [95% CI: 60.6, 74.2], with a CR + CRi rate of 8%, nPR rate of 6%, and PR rate of 53%. Median DOR was not reached with median follow-up of approximately 23.8 months. The IRC-assessed ORR for patients treated with venetoclax + rituximab was 92% [95% CI: 87.6, 95.6], with a CR + CRi rate of 8%, nPR rate of 2%, and PR rate of 82%. For patients treated with bendamustine + rituximab, IRC-assessed ORR was 72% [95% CI: 65.5, 78.5], with a CR + CRi rate of 4%, nPR rate of 1%, and PR rate of 68%. The discrepancy between IRC- and investigator-assessed CR rates was due to interpretation of residual adenopathy on CT scans. Eighteen patients in the venetoclax + rituximab arm and 3 patients in the bendamustine + rituximab arm had negative bone marrow and lymph nodes <2 cm.

Minimal residual disease (MRD) at the end of combination treatment was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry. MRD negativity was defined as less than one CLL cell per 104 leukocytes. MRD negativity rates in peripheral blood were 62% (95% CI: 55.2, 69.2) in the venetoclax + rituximab arm compared to 13% (95% CI: 8.9, 18.9) in the bendamustine + rituximab arm. Of those with MRD assay results available in peripheral blood, 72% (121/167) in the venetoclax + rituximab arm and 20% (26/128) in the bendamustine + rituximab arm were found to be MRD negative. MRD negativity rates in the bone marrow were 16% (95% CI: 10.7, 21.3) in the venetoclax + rituximab arm and 1% (95% CI: 0.1, 3.7) in the bendamustine + rituximab arm. Of those with MRD assay results available in bone marrow, 77% (30/39) in the venetoclax + rituximab arm and 7% (2/30) in the bendamustine + rituximab arm were found to be MRD negative.

Median OS had not been reached in either treatment arm. Death occurred in 8% (15/194) of patients treated with venetoclax + rituximab and 14% (27/195) of patients treated with bendamustine + rituximab (hazard ratio: 0.48 [95% CI: 0.25, 0.90]).

By the data cut-off date, 12% (23/194) of patients in the venetoclax + rituximab arm and 43% (83/195) of patients in the bendamustine + rituximab arm had started a new anti-leukaemic treatment or died (stratified hazard ratio: 0.19; [95% CI: 0.12, 0.31]). The median time to new anti-leukaemic treatment or death was not reached in the venetoclax + rituximab arm and was 26.4 months in the bendamustine + rituximab arm.

59-month follow-up

Efficacy was assessed after a median follow-up of 59 months (data cut-off date 8 May 2020). Efficacy results for the MURANO 59-month follow-up are presented in Table 12.

Table 12: Investigator-assessed efficacy results in MURANO (59-month

follow-up)__________­________________________­________________________­__

In total, 130 patients in the venetoclax + rituximab arm completed 2 years of venetoclax treatment without progression. For these patients, the 3-year PFS estimate post-treatment was 51% [95 % CI: 40.2, 61.9].

The Kaplan-Meier curve of investigator-assessed PFS is shown in Figure 2.

Figure 2: Kaplan-Meier curve of investigator-assessed progression-free survival (intent-to-treat population) in MURANO (data cut-off date 8 May 2020) with 59-month follow-up

The Kaplan-Meier curve of overall survival is shown in Figure 3.

Figure 3: Kaplan-Meier curve of overall survival (intent-to-treat population) in MURANO (data cut-off date 8 May 2020) with 59-month follow-up

Results of subgroup analyses

The observed PFS benefit of venetoclax + rituximab compared with

bendamustine + rituximab was consistently observed across all subgroups of patients evaluated, including high-risk patients with deletion 17p/TP53 mutation and/or unmutated IgVH (Figure 4).

Figure 4: Forest plot of investigator-assessed progression-free survival in subgroups from MURANO (data cut-off date 8 May 2020) with 59-month follow-up

1/100            1             100

17p deletion status was determined based on central laboratory test results.

Unstratified hazard ratio is displayed on the X-axis with logarithmic scale.

NE=not evaluable.

Venetoclax as monotherapy for the treatment of patients with CLL harbouring 17p deletion or TP53 mutation – study M13–982

The safety and efficacy of venetoclax in 107 patients with previously treated CLL with 17p deletion were evaluated in a single-arm, open-label, multi-center study (M13–982). Patients followed a 4– to 5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed. The median age was 67 years (range: 37 to 85 years); 65% were male, and 97% were white. The median time since diagnosis was 6.8 years (range: 0.1 to 32 years; N=106). The median number of prior anti-CLL treatments was 2 (range: 1 to 10 treatments); 49.5% with a prior nucleoside analogue, 38% with prior rituximab, and 94% with a prior alkylator (including 33% with prior bendamustine). At baseline, 53% of patients had one or more nodes >5 cm, and 51% had ALC >25 × 109/1. Of the patients, 37% (34/91) were fludarabine refractory, 81% (30/37) harboured the unmutated IgVH gene, and 72% (60/83) had TP53 mutation. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months).

The primary efficacy endpoint was overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the IWCLL updated NCI-WG guidelines (2008). Efficacy results are shown in Table 13. Efficacy data are presented for 107 patients with data cutoff date 30 April 2015. An additional 51 patients were enrolled in a safety expansion cohort. Investigator-assessed efficacy results are presented for 158 patients with a later data cutoff date 10 June 2016. The median time on treatment for 158 patients was 17 months (range: 0 to 34 months).

Table 13: Efficacy results in patients with previously treated CLL with 17p deletion (study M13–982)

Minimal residual disease (MRD) was evaluated using flow cytometry in 93 of 158 patients who achieved complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) with limited remaining disease with venetoclax treatment. MRD negativity was defined as a result below 0.0001 (<1 CLL cell per 104 leukocytes in the sample). Twenty-seven percent (42/158) of patients were MRD negative in the peripheral blood, including 16 patients who were also MRD negative in the bone marrow.

Venetoclax as monotherapy for the treatment of patients with CLL who have failed a B-cell receptor pathway inhibitor – study M14–032

The efficacy and safety of venetoclax in patients with CLL who had been previously treated with and failed ibrutinib or idelalisib therapy were evaluated in an open-label, multi-center, non-randomised, phase 2 study (M14–032). Patients received venetoclax via a recommended dose-titration schedule. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed.

At the time of data cut-off (26 July 2017), 127 patients were enrolled and treated with venetoclax. Of these, 91 patients had received prior ibrutinib therapy (Arm A) and 36 had received prior idelalisib therapy (Arm B). The median age was 66 years (range: 28 to 85 years), 70% were male, and 92% were white. The median time since diagnosis was 8.3 years (range: 0.3 to 18.5 years; N=96). Chromosomal aberrations were 11q deletion (34%, 43/127), 17p deletion (40%, 50/126), TP53 mutation (38%, 26/68) and unmutated IgVH (78%, 72/92). At baseline, 41% of patients had one or more nodes >5 cm and 31% had ALC >25 × 109/1. The median number of prior oncology treatments was 4 (range: 1 to 15) in ibrutinib-treated patients and 3 (range: 1 to 11) in idelalisib-treated patients. Overall, 65% of patients received prior nucleoside analogue, 86% rituximab, 39% other monoclonal antibodies, and 72% alkylating agent (including 41% with bendamustine). At the time of evaluation, median duration of treatment with venetoclax was 14.3 months (range: 0.1 to 31.4 months).

The primary efficacy endpoint was ORR according to IWCLL updated NCI-WG guidelines. Response assessments were performed at 8 weeks, 24 weeks, and every 12 weeks thereafter.

Table 14: Efficacy results as assessed by investigator in patients who have failed a B-cell receptor pathway inhibitor (study M14–032)

The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 70% (Arm A: 70%; Arm B: 69%). One patient (ibrutinib failure) achieved complete remission with incomplete marrow recovery. The ORR for patients with 17p deletion and/or TP53 mutation was 72% (33/46) (95% CI: 56.5, 84.0) in Arm A and 67% (8/12) (95% CI: 34.9, 90.1) in Arm B. For patients without 17p deletion and/or TP53 mutation, the ORR was 69% (31/45) (95% CI: 53.4, 81.8) in Arm A and 71% (17/24) (95% CI: 48.9, 87.4) in Arm B.

Median OS and DOR were not reached with median follow-up of approximately 14.3 months for Arm A and 14.7 months for Arm B.

Twenty-five percent (32/127) of patients were MRD negative in the peripheral blood, including 8 patients who were also MRD negative in bone marrow.

Acute Myeloid Leukaemia

Venetoclax was studied in adult patients who were > 75 years of age, or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2–3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, creatinine clearance (CLcr) < 45 mL/min, or other comorbidity.

Venetoclax in combination with azacitidine for the treatment of patients with newly diagnosed AML – study M15–656 (VIALE-A)

VIALE-A was a randomised (2:1), double-blind, placebo-controlled phase 3 study that evaluated the efficacy and safety of venetoclax in combination with azacitidine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy.

Patients in VIALE-A completed the 3-day daily titration schedule to a final 400 mg once daily dose during the first 28-day cycle of treatment (see section 4.2) and received venetoclax 400 mg orally once daily thereafter in subsequent cycles.

Azacitidine at 75 mg/m2 was administered either intravenously or subcutaneously on Days 1–7 of each 28-day cycle beginning on Cycle 1 Day 1. During the titration, patients received TLS prophylaxis and were hospitalised for monitoring. Once bone marrow assessment confirmed a remission, defined as less than 5% leukaemia blasts with grade 4 cytopenia following Cycle 1 treatment, venetoclax or placebo was

interrupted up to 14 days or until ANC >500/microlitre and platelet count >50 × 103/ microlitre. For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated. Azacitidine was resumed on the same day as venetoclax or placebo following interruption (see section 4.2). Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity (see azacitidine Summary of Product Characteristics). Patients continued to receive treatment cycles until disease progression or unacceptable toxicity.

A total of 431 patients were randomised: 286 to the venetoclax + azacitidine arm and 145 to the placebo + azacitidine arm. Baseline demographic and disease characteristics were similar between the venetoclax + azacitidine and placebo + azacitidine arms. Overall, the median age was 76 years (range: 49 to 91 years), 76% were white, 60% were males, and ECOG performance status at baseline was 0 or 1 for 55% of patients, 2 for 40% of patients and 3 for 5% of patients. There were 75% of patients with de novo AML and 25% with secondary AML. At baseline, 29% of patients had bone marrow blast count <30%, 22% of patients had bone marrow blast count >30% to <50%, and 49% had >50%. Intermediate or poor cytogenetic risk was present in 63% and 37% patients, respectively. The following mutations were identified: TP53 mutations in 21% (52/249), IDH1 and/or IDH2 mutation in 24% (89/372), 9% (34/372) with IDH1; 16% (58/372) with IDH2, 16% (51/314) with FLT3, and 18% (44/249) with NPM1.

The primary efficacy endpoints of the study were overall survival (OS), measured from the date of randomisation to death from any cause and composite complete remission rate (complete remission + complete remission with incomplete blood count recovery [CR+CRi]). The overall median follow-up at the time of analysis was 20.5 months (range: <0.1 to 30.7 months).

Venetoclax + azacitidine demonstrated a 34% reduction in the risk of death compared with placebo + azacitidine (P <0.001). Results are shown in Table 15.

Table 15: Efficacy results in VIALE-A

Figure 5: Kaplan-Meier curve for overall survival in VIALE-A

Key secondary efficacy endpoints are presented in Table 16.

Table 16: Additional efficacy endpoints in VIALE-A

Endpoint

Venetoclax + azacitidine

Placebo + azacitidine

CI = confidence interval; CR = complete remission; CRi = complete remission with

incomplete blood count recovery; DOR = duration of response; EFS = event-free survival; MRD = minimal/measurable residual disease; n = number of responses or number of events; – = not reached.

CR (complete remission) was defined as absolute neutrophil count >1,000/microlitre, platelets >100,000/micro­litre, red blood cell transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease.

Transfusion independence was defined as a period of at least consecutive 56 days (>56 days) with no transfusion after the first dose of study drug and on or before the last dose of the study drug + 30 days, or before relapse or disease progression or before the initiation of post treatment therapy whichever is earlier.

aP-value is from Cochran-Mantel-Haenszel test stratified by age (18 to <75, >75) and cytogenetic risk (intermediate risk, poor risk) as assigned at randomisation.

bDOR (duration of response) was defined as time from first response of CR for DoR of CR, from first response of CR or CRi for DoR of CR+CRi, to the first date of confirmed morphologic relapse, confirmed progressive disease or death due to disease progression, whichever occurred earlier. Median DOR is from Kaplan-Meier estimate.

cHazard ratio estimate (venetoclax + azacitidine vs. placebo + azacitidine)_is based on Coxproportional hazards model stratified by age (18 to <75, >75) and cytogenetics (intermediate risk, poor risk) as assigned at randomisation; p-value based on log-rank test stratified by the same factors.

d CR+CRi MRD response rate is defined as the % of patients achieving a CR or CRi and demonstrated an MRD response of <10–3 blasts in bone marrow as determined by a standardized, central multicolour flow cytometry assay.

eKaplan-Meier estimate.

Of patients with the FLT3 mutation, the CR+CRi rates were 72% (21/29; [95% CI: 53, 87]) and 36% (8/22; [95% CI: 17, 59]) in the venetoclax + azacitidine and placebo + azacitidine arms, respectively (p=0.021).

Of patients with IDH1/IDH2 mutations, the CR+CRi rates were 75% (46/61; [95% CI: 63, 86]) and 11% (3/28; [95% CI: 2, 28]) in the venetoclax + azacitidine and placebo + azacitidine arms, respectively (p<0.001).

Of the patients who were RBC transfusion dependent at baseline and treated with venetoclax + azacitidine, 49% (71/144) became transfusion independent. Of the patients who were platelet transfusion dependent at baseline and treated with venetoclax + azacitidine, 50% (34/68) became transfusion independent.

The median time to first response of CR or CRi was 1.3 months (range: 0.6 to 9.9 months) with venetoclax + azacitidine treatment. The median time to best response of CR or CRi was 2.3 months (range: 0.6 to 24.5 months).

Figure 6: Forest plot of overall survival by subgroups from VIALE-A

– = Not reached.

For the pre-specified secondary endpoint OS in the IDH1/2 mutation subgroup, p<0.0001 (unstratified log-rank test).

Unstratified hazard ratio (HR) is displayed on the X-axis with logarithmic scale.

Venetoclax in combination with azacitidine or decitabine for the treatment of patients with newly diagnosed AML – M14–358

Study M14–358 was a non-randomised phase 1/2 clinical trial of venetoclax in combination with azacitidine (n=84) or decitabine (n=31) in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. Patients received venetoclax via a daily titration to a final 400 mg once daily dose. The administration of azacitidine in M14–358 was similar to that of VIALE-A randomised study.

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

The median follow-up was 40.4 months (range: 0.7 to 42.7 months) for venetoclax + decitabine.

The median age of patients treated with venetoclax + decitabine was 72 years (range: 65–86 years), 87% were white, 48% males, and 87% had ECOG score 0 or 1. The CR+CRi rate was 74% (95%CI: 55, 88) in combination with decitabine.

Venetoclax in combination with low-dose cytarabine for the treatment of patients with newly-diagnosed AML study – M16–043 (VIALE-C)

VIALE-C was a randomised (2:1), double-blind, placebo-controlled phase 3 study that evaluated the efficacy and safety of venetoclax in combination with low-dose cytarabine in patients with newly-diagnosed AML who were ineligible for intensive chemotherapy.

Patients in VIALE-C completed 4-day titration schedule to a final 600 mg once daily dose during first cycle of treatment (see section 4.2) and received venetoclax 600 mg orally once daily on Days 1–28 plus low-dose cytarabine 20 mg/m2 subcutaneously (SC) once daily on Days 1–10. Placebo orally once daily was administered on Days 1–28 plus low-dose cytarabine 20 mg/m2 SC once daily on Days 1–10. During the titration, patients received TLS prophylaxis and were hospitalised for monitoring. Once bone marrow assessment confirmed a remission, defined as less than 5% leukaemia blasts with grade 4 cytopenia following Cycle 1 treatment, venetoclax or placebo was interrupted up to 14 days or until ANC >500/microlitre and platelet count > 25 × 103/mi­crolitre. For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle2 or 3 and as clinically indicated. Low-dose cytarabine was resumed on the same day as venetoclax or placebo following interruption._Pa­tients continued to receive treatment cycles until disease progression or unacceptable toxicity. Dose reduction for low-dose cytarabine was not implemented in the clinical trial.

A total of211 patients were randomised: 143 to the venetoclax in combination with low-dose cytarabine arm and 68 to the placebo in combination with low-dose cytarabine arm. Baseline demographic and disease characteristics were similar between the venetoclax + low-dose cytarabine and placebo + low-dose cytarabine arms. The median age was 76 years (range: 36 to 93 years); 55% were male, 71% were white, and ECOG performance status at baseline was 0 or 1 for 51% of patients, for 42%, and 3 for 7% of patients. There were 62% of patients with de novo AML and 38% with secondary AML. At baseline,27% of patients had bone marrow blast count >30% – <50%, and 44% had >50%. Intermediate or poor cytogenetic risk was present in 63% and 32% patients, respectively. The following mutations were detected among 164 patients with samples: 19% (31) with TP53,20% (33) with IDH1 or IDH2, 18% (29) with FLT3, and 15% (25) with NPM1.

At the time of the primary analysis for OS, patients had a median follow-up of 12 months (range: 0.1 to 17.6 months). The median OS in the venetoclax + low-dose cytarabine arm was 7.2 months (95% CI: 5.6, 10.1) and in the placebo + low-dose cytarabine arm was 4.1 months (95% CI: 3.1, 8.8). The hazard ratio was 0.75 (95% CI: 0.52, 1.07; p = 0.114) representing a25% reduction in the risk of death for patients treated with venetoclax + low-dose cytarabine.

Figure 7: Kaplan-Meier curves of overall survival (primary analysis) in VIALE-C

At the time of an additional analysis for OS, patients had a median follow-up of 17.5 months (range: 0.1 to 23.5 months). The median OS in the venetoclax + low-dose cytarabine arm was 8.4 months (95% CI: 5.9, 10.1) and in the placebo + low-dose cytarabine arm was 4.1 months (95% CI: 3.1, 8.1). The hazard ratio was 0.70 (95% CI: 0.50, 0.99, nominal p= 0.040) representing a 30% reduction in the risk of death for patients treated with venetoclax + low-dose cytarabine.

Figure 8: Kaplan-Meier curves of overall survival (6-month follow-up analysis) in VIALE-C

In the additional 24-month analysis for OS, the median OS in the venetoclax + low-dose cytarabine arm was 8.4 months (95% CI: 5.9, 10.3) and in the placebo + low-dose cytarabine arm was 4.1 months (95% CI: 3.1, 8.1). The hazard ratio was 0.71 (95% CI: 0.52, 0.98, nominal p= 0.036) representing a 29% reduction in the risk of death for patients treated with venetoclax + low-dose cytarabine.

Figure 9: Kaplan-Meier curves of overall survival (24-month follow-up analysis) in VIALE-C

Efficacy results for secondary endpoints from the primary analysis are shown in Table 17 below.

Table 17: Efficacy results for secondary endpoints from the primary analysis of VIALE-C

The CR+CRi rate by initiation of Cycle 2 for venetoclax + low-dose cytarabine was 34% (95% CI: 27, 43) and for placebo + low-dose cytarabine was 3% (95% CI: 0.4, 10). The median time to first response of CR+CRi was 1.1 month (range: 0.8 to 4.7 months) with venetoclax + low-dose cytarabine treatment. The median time to best response of CR+CRi was 1.2 month (range: 0.8 to 5.9 months).

In the additional 24-months follow up analysis, CR+CRi rates for venetoclax + low-dose cytarabine was 48% (95% CI: 40, 57) and for placebo + low-dose cytarabine was 13% (95% CI: 6, 24), as per Investigator Assessment.

Minimal residual disease (MRD) response was defined as less than one AML cell per 103 leukocytes in the bone marrow. For the patients who had MRD assessment (113 patients in venetoclax + low-dose cytarabine arm and 44 in placebo + low-dose cytarabine arm), the median MRD value (%) was lower in the venetoclax arm when compared to the placebo arm (0.42 and 7.45, respectively). A higher number of patients had achieved CR+CRi and MRD response on venetoclax arm compared to placebo arm: 8 patients (6%) (95% CI: 2, 11) versus 1 patient (1%) (95% CI: 0, 8), respectively.

Patient-reported fatigue was assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS), Cancer Fatigue Short Form (SF 7a) and health-related quality of life (HRQoL) was assessed by the EORTC QLQ-C30 global health status/quality of life (GHS/QoL). Patients receiving venetoclax + low-dose cytarabine did not experience meaningful decrement in fatigue or HRQoL than placebo + low-dose cytarabine, and observed reduction in PROMIS Cancer Fatigue SF 7a and improvement in GHS/QoL up to Cycle 9. Relative to placebo + low-dose cytarabine, patients receiving venetoclax + low-dose cytarabine observed reduction in PROMIS Cancer Fatigue SF 7a that achieved a minimum important difference (MID) between two arms of 3 points by Day 1 of Cycles 3 and 5 (-2.940 versus 1.567, –5.259 versus –0.336, respectively, with lower score indicating improvement in fatigue symptom).

Patients receiving venetoclax + low-dose cytarabine observed improvement in GHS/QoL that achieved a MID of 5 points on Day 1 of Cycles 5, 7 and 9 vs placebo + low-dose cytarabine (16.015 vs 2.627, 10.599 vs 3.481, and 13.299 vs 6.918, respectively, with higher score indicating improvement in quality of life).

Elderly patients

Of the 194 patients with previously treated CLL who received venetoclax in combination with rituximab, 50% were 65 years or older.

Of the 107 patients who were evaluated for efficacy from M13–982 study, 57% were 65 years or older. Of the 127 patients who were evaluated for efficacy from M14–032 study, 58% were 65 years or older.

Of the 352 patients evaluated for safety from 3 open-label monotherapy trials, 57% were 65 years or older.

Of the 283 patients with newly diagnosed AML treated in the VIALE-A (venetoclax + azacitidine arm) clinical trial, 96% were >65 years of age and 60% were >75 years of age. Of the 31 patients treated with venetoclax in combination with decitabine in the M14–358 clinical trial, 100% were >65 years of age and 26% were >75 years of age. Of the 142 patients treated in the VIALE-C (venetoclax + low-dose cytarabine arm) clinical trial, 92% were >65 years of age and 57% were >75 years of age.

There were no clinically meaningful differences in safety or efficacy observed between older and younger patients in the combination and monotherapy studies.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Venclyxto in all subsets of the paediatric population in CLL (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with Venclyxto in one or more subsets of the paediatric population in AML (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 jig/ml and AUC24 was 32.8 ± 16.9 pg^h/ml at the 400 mg once daily dose, and 2.7 ± 1.6 jig/ml and 45.6 ± 30.6 pg^h/ml, respectively, at the 600 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 pM (0.87–26 pg/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

Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and a weak OATP1B1 inhibitor in vitro (see section 4.5). Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K at clinically relevant concentrations.

Elimination

The population estimate for the terminal phase elimination half-life of venetoclax was approximately 26 hours. Venetoclax shows minimal accumulation with accumulation ratio of 1.30–1.44. After a single oral administration of 200 mg radiolabeled [14C]-venetoclax to healthy subjects, >99.9% of the dose was recovered in faeces and <0.1% of the dose was excreted in urine within 9 days. Unchanged venetoclax accounted for 20.8% of the administered radioactive dose excreted in faeces. The pharmacokinetics of venetoclax do not change over time.

Special populations

Renal impairment

Based on a population pharmacokinetic analysis that included 321 subjects with mild renal impairment (CrCl >60 and <90 ml/min), 219 subjects with moderate renal impairment (CrCl >30 and <60 ml/min), 5 subjects with severe renal impairment (CrCl >15 and <30 ml/min) and 224 subjects with normal renal function (CrCl >90 ml/min), venetoclax exposures in subjects with mild, moderate or severe renal impairment are similar to those with normal renal function. The pharmacokinetics of venetoclax has not been studied in subjects with CrCl <15 ml/min or patients on dialysis (see section 4.2).

Hepatic impairment

Based on a population pharmacokinetic analysis that included 74 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 442 subjects with normal hepatic function, venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 ULN.

In a dedicated hepatic impairment study, venetoclax Cmax and AUC in subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=6) hepatic impairment were similar to subjects with normal hepatic function, after receiving a 50 mg single dose of venetoclax. In subjects with severe (Child-Pugh C; n=5) hepatic impairment, the mean venetoclax Cmax was similar to subjects with normal hepatic function but venetoclax AUCinf was on average 2.7-fold higher (range: no change to 5-fold higher) than venetoclax AUCinf in the subjects with normal hepatic function (see section 4.2).

Effects of age, sex, weight and race

Based on population pharmacokinetic analyses, age, sex, and weight do not have an effect on venetoclax clearance. The exposure is 67% higher in Asian subjects as compared to non-Asian subjects. This difference is not considered clinically relevant.

5.3 Preclinical safety data

Toxicities observed in animal studies with venetoclax included dose-dependent reductions in lymphocytes and red blood cell mass. Both effects were reversible after cessation of dosing with venetoclax, with recovery of lymphocytes occurring 18 weeks post treatment. Both B- and T-cells were affected, but the most significant decreases occurred with B-cells.

Venetoclax also caused single cell necrosis in various tissues, including the gallbladder and exocrine pancreas, with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude.

After approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment in the hair.

Carcinogenici­ty/genotoxici­ty

Venetoclax and the M27 major human metabolite were not carcinogenic in a 6-month transgenic (Tg.rasH2) mouse carcinogenicity study at oral doses up to 400 mg/kg/day of venetoclax and at a single dose level of 250 mg/kg/day of M27. Exposure margins (AUC), relative to the clinical AUC at 400 mg/day, were approximately 2-fold for venetoclax and 5.8-fold for M27.

Venetoclax was not genotoxic in bacterial mutagenicity assay, in vitro chromosome aberration assay and in vivo mouse micronucleus assay. The M27 metabolite was negative for genotoxicity in the bacterial mutagenicity and chromosomal aberration assays.

Reproductive toxicity

No effects on fertility were observed in fertility and early embryonic development studies in male and female mice. Testicular toxicity (germ cell loss) was observed in general toxicity studies in dogs at exposures of 0.5 to 18 times the human AUC exposure at a dose of 400 mg. Reversibility of this finding has not been demonstrated.

In embryo-foetal development studies in mice, venetoclax was associated with increased post-implantation loss and decreased foetal body weight at exposures of 1.1 times the human AUC exposure at a dose of 400 mg. The major human metabolite M27 was associated with post-implantation loss and resorptions at exposures approximately 9-times the human M27-AUC exposure at a 400 mg dose of venetoclax. In rabbits, venetoclax produced maternal toxicity, but no foetal toxicity at exposures of 0.1 times the human AUC exposure at a 400 mg dose.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Copovidone (K 28)

Colloidal anhydrous silica (E551)

Polysorbate 80 (E433)

Sodium stearyl fumarate

Anhydrous calcium hydrogen phosphate (E341 (ii))

Film-coating

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172) Polyvinyl alcohol (E1203) Titanium dioxide (E171) Macrogol 3350 (E1521)

Talc (E553b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Venclyxto film-coated tablets are supplied in PVC/PE/PCTFE aluminium foil blisters containing either 1, 2 or 4 film-coated tablets.

The film-coated tablets are supplied in cartons containing either 5 or 7 tablets (in blisters of 1 tablet).

Not all pack sizes may be marketed.