VENCLYXTO 100mg tablets medication leaflet

Venclyxto 10 mg film-coated tablets

Venclyxto 50 mg film-coated tablets

Venclyxto 100 mg film-coated tablets

Venclyxto 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of venetoclax.

Venclyxto 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of venetoclax.

Venclyxto 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of venetoclax.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Venclyxto 10 mg film-coated tablet

Pale yellow, round biconvex shaped tablet 6 mm diameter debossed with V on one side and 10 on theother.

Venclyxto 50 mg film-coated tablet

Beige, oblong biconvex shaped tablet 14 mm long, 8 mm wide debossed with V on one side and 50 onthe other.

Venclyxto 100 mg film-coated tablet

Pale yellow, oblong biconvex shaped tablet 17.2 mm long, 9.5 mm wide debossed with V on one sideand 100 on the other.

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

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL whohave 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 orhave failed a B-cell receptor pathway inhibitor, or

* in the absence of 17p deletion or TP53 mutation in adult patients who have failed bothchemoimmunotherapy and a B-cell receptor pathway inhibitor.

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

Treatment with venetoclax should be initiated and supervised by a physician experienced in the use ofanticancer 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 andreduce the risk of TLS.

Chronic lymphocytic leukaemia

Dose-titration schedule

The starting dose is 20 mg of venetoclax once daily for 7 days. The dose must be gradually increasedover 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 dose1 20 mg2 50 mg3 100 mg4 200 mg5 400 mg

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

Venetoclax in combination with obinutuzumab

Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combinationwith 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 administeredon Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of eachsubsequent 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 continuethrough Cycle 2 Day 28.

After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg oncedaily 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 section5.1 for details of the combination regimen).

Administer rituximab after the patient has completed the dose-titration schedule and has received therecommended 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 diseaseprogression or no longer tolerated by the patient.

Acute myeloid leukaemia

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

Table 2: Dose increase schedule in patients with AML

Day Venetoclax daily dose1 100 mg2 200 mg3 and beyond 400 mg

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

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

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

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

Prevention of tumour lysis syndrome (TLS)

Patients treated with venetoclax may develop TLS. The appropriate section below should be referredto 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-weekdose-titration phase in all patients with CLL, regardless of tumour burden and other patientcharacteristics. Changes in electrolytes consistent with TLS that require prompt management canoccur 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 andanti-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, particularlyreduced renal function (creatinine clearance [CrCl] <80ml/min), and tumour burden. Splenomegalymay contribute to the overall TLS risk. The risk may decrease as tumour burden decreases withvenetoclax treatment (see section 4.4).

Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation (e.g., CTscan), 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 venetoclaxtreatment 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, eitheroutpatient or in hospital.

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

Blood chemistry

Tumour burden Prophylaxis c,dmonitoring

Setting anda Anti-

Hydration b frequency ofhyperuricaemicsassessments

Low All LN <5 cm Oral Allopurinol Outpatient

AND (1.5-2 L) * For first dose of

ALC <25 x109/L 20 mg and 50 mg:

Pre-dose, 6 to 8 hours,24 hours

* For subsequent doseincreases: Pre-dose

Medium Any LN 5 cm to Oral Allopurinol Outpatient<10 cm (1.5-2 L) * For first dose of

OR and consider 20 mg and 50 mg:

ALC ≥25 x109/L additional Pre-dose, 6 to 8 hours,intravenous 24 hours

* For subsequent doseincreases: Pre-dose

* For first dose of20 mg and 50 mg:

Considerhospitalisation forpatients with CrCl<80ml/min; see belowfor monitoring inhospital

High Any LN ≥10 cm Oral (1.5-2 L) Allopurinol; In hospital

OR and intravenous consider rasburicase * For first dose of

ALC ≥25 x109/L (150-200 ml/hr if baseline uric acid 20 mg and 50 mg:

AND as tolerated) is elevated Pre-dose, 4, 8, 12 andany LN ≥5 cm 24 hours

Outpatient

* For subsequent doseincreases: Pre-dose, 6to 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, specificallyprior to and on the days of dosing at initiation and each subsequent dose increase. Administer intravenoushydration 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 whocontinue 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 forrecommended dose modifications for toxicities related to venetoclax.

Table 4: Recommended venetoclax dose modifications for toxicitiesa in CLL

Event Occurrence Action

Blood chemistry changes Any Withhold the next day’s dose. If resolved withinor symptoms suggestive 24 to 48 hours of last dose, resume at the sameof TLS dose.

For any blood chemistry changes requiring morethan 48 hours to resolve, resume at a reduced dose(see Table 5).

For any events of clinical TLS,b resume at areduced dose following resolution (see Table 5).

Non-haematologic toxicities

Grade 3 or 4 non- 1st occurrence Interrupt venetoclax.haematologic toxicities Once the toxicity has resolved to Grade 1 orbaseline level, venetoclax therapy may beresumed at the same dose. No dose modificationis required.

2nd and subsequent Interrupt venetoclax.occurrences Follow dose reduction guidelines in Table 5 whenresuming treatment with venetoclax afterresolution. A larger dose reduction may occur atthe discretion of the physician.

Haematologic toxicities

Grade 3 neutropenia with 1st occurrence Interrupt venetoclax.infection or fever; or To reduce the infection risks associated with

Grade 4 haematologic neutropenia, granulocyte-colony stimulatingtoxicities (except factor (G-CSF) may be administered withlymphopenia) venetoclax if clinically indicated. Once thetoxicity has resolved to Grade 1 or baseline level,venetoclax therapy may be resumed at the samedose.

2nd and subsequent Interrupt venetoclax.occurrences Consider using G-CSF as clinically indicated.

Follow dose reduction guidelines in Table 5 whenresuming treatment with venetoclax afterresolution. A larger dose reduction may occur atthe discretion of the physician.

Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg formore 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 Restart dosea(mg) (mg )400 300300 200200 100100 5050 2020 10aThe modified dose should be continued for 1 week beforeincreasing the dose.

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

Acute myeloid leukaemia

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

Prophylaxis measures listed below should be followed:

All patients should have white blood cell count <25 × 109/l prior to initiation of venetoclax andcytoreduction prior to treatment may be required.

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

Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correctpre-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 and24 hours after reaching final dose.

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

Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptionsfor cytopenias are dependent on remission status. Dose modifications of venetoclax for adversereactions 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 Occurrence prior to achieving In most instances, do not interrupt venetoclax(ANC < 500/microlitre) remissiona in combination with azacitidine or decitabinewith or without fever or due to cytopenias prior to achievinginfection; or grade 4 remission.

thrombocytopenia First occurrence after Delay subsequent cycle of venetoclax in(platelet count <25 × achieving remission and combination with azacitidine or decitabine103/microlitre) lasting at least 7 days and monitor blood counts. Administergranulocyte-colony stimulating factor (G-

CSF) if clinically indicated for neutropenia.

Upon resolution to grade 1 or 2, resumevenetoclax at the same dose in combinationwith azacitidine or decitabine.

Subsequent occurrences in Delay subsequent cycle of venetoclax incycles after achieving combination with azacitidine or decitabineremission and lasting 7 days and monitor blood counts. Administer G-CSFor longer if clinically indicated for neutropenia.

Upon resolution to grade 1 or 2, resumevenetoclax at the same dose in combinationwith azacitidine or decitabine, and reducevenetoclax duration by 7 days during each ofthe subsequent cycles, such as 21 daysinstead of 28 days.

Refer to the azacitidine prescribinginformation for additional information.

Non-Hematologic Adverse Reactions

Grade 3 or 4 non- Any occurrence Interrupt venetoclax if not resolved withhematologic toxicities 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 venetoclaxexposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during thedose-titration phase and for other toxicities (see section 4.5).

In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors is contraindicatedat initiation and during the dose-titration phase (see sections pct. 4.3, pct. 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 oftoxicities and the dose may need to be further adjusted. The venetoclax dose that was used prior toinitiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor (seesections pct. 4.3, pct. 4.4 and 4.5).

Table 7: Management of potential venetoclax interactions with CYP3A inhibitors

Inhibitor Phase CLL AML

Day 1 - 10 mg

Initiation and dose-

Day 2 - 20 mgtitration Contraindicated

Day 3 - 50 mg

Strong CYP3A phase

Day 4 - 100 mg or lessinhibitor

Steady daily dose Reduce the venetoclax dose to 100 mg or less(After dose-titration (or by at least 75% if already modified for otherphase) reasons)

Moderate CYP3Aa All Reduce the venetoclax dose by at least 50%inhibitoraIn patients with CLL, avoid concomitant use of venetoclax with moderate CYP3A inhibitors atinitiation and during the dose-titration phase. Consider alternative medicinal products or reduce thevenetoclax dose as described in this table.

If a patient misses a dose of venetoclax within 8 hours of the time it is usually taken, the patient shouldtake the missed dose as soon as possible on the same day. If a patient misses a dose by more than 8hours, the patient should not take the missed dose and should resume the usual dosing schedule thefollowing day.

If a patient vomits following dosing, no additional dose should be taken that day. The next prescribeddose should be taken at the usual time the following day.

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

Patients with reduced renal function (CrCl <80 ml/min) may require more intensive prophylaxis andmonitoring to reduce the risk of TLS at initiation and during the dose-titration phase (see “Preventionof tumour lysis syndrome (TLS)” above). Venetoclax should be administered to patients with severerenal impairment (CrCl ≥15 ml/min and <30 ml/min) only if the benefit outweighs the risk andpatients should be monitored closely for signs of toxicity due to increased risk of TLS (see section4.4).

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).

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

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

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 aposology can be made.

Venclyxto film-coated tablets are for oral use. Patients should be instructed to swallow the tabletswhole with water at approximately the same time each day. The tablets should be taken with a meal inorder 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 laboratorymonitoring.

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

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

In patients with CLL, concomitant use of strong CYP3A inhibitors at initiation and during thedose-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).

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

Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS at initiation and duringthe dose-titration phase. Changes in electrolytes consistent with TLS that require prompt managementcan 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 single20 mg dose of venetoclax. Information described in section 4.2, including risk assessment,prophylactic measures, dose-titration and modification schedule, laboratory monitoring, and druginteractions should be followed to prevent and reduce the risk of TLS.

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

All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, includinghydration and anti-hyperuricaemics. Blood chemistries should be monitored, and abnormalitiesmanaged 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 (seesection 4.2).

Concomitant use of this medicinal product with strong or moderate CYP3A inhibitors increasesvenetoclax 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 (seesection 4.5).

Neutropenia and infections

In patients with CLL, grade 3 or 4 neutropenia has been reported in patients treated with venetoclax incombination 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 neutrophilcounts can worsen with venetoclax in combination with a hypomethylating agent. Neutropenia canrecur with subsequent cycles of therapy.

Complete blood counts should be monitored throughout the treatment period. Dose interruptions orreductions 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 receiveprompt treatment, including antimicrobials, dose interruption or reduction, and use of growth factors(e.g., G-CSF) as appropriate (see section 4.2).

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

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

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

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

Venetoclax is predominantly metabolised by CYP3A.

Agents that may alter venetoclax plasma concentrations

Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for7 days in 11 patients increased venetoclax Cmax to 2.3-fold and AUC to 6.4-fold. Co-administration of50 mg once daily ritonavir, a strong CYP3A and P-gp inhibitor, for 14 days in 6 healthy subjectsincreased venetoclax Cmax to 2.4-fold and AUC by 7.9-fold. Compared with venetoclax 400 mgadministered 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 and1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively. Co-administration of venetoclax with otherstrong 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 beadministered according to Table 7. Patients should be monitored more closely for signs of toxicitiesand 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 treatmentwith 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 ofrifampicin, a P-gp inhibitor, in 11 healthy subjects increased venetoclax Cmax by 106% and AUC by78%. Concomitant use of venetoclax with P-gp and BCRP inhibitors at initiation and during thedose-titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should bemonitored closely for signs of toxicities (see section 4.4).

Co-administration of 600 mg once daily rifampicin, a strong CYP3A inducer, for 13 days in 10healthy subjects decreased venetoclax Cmax by 42% and AUC by 71%. Concomitant use of venetoclaxwith strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampicin) or moderate CYP3Ainducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. Alternativetreatments with less CYP3A induction should be considered. Preparations containing St. John's wortare 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 azithromycinon the first day followed by 250 mg of azithromycin once daily for 4 days decreased venetoclax Cmaxby 25% and AUC by 35%. No dose adjustment is needed during short-term use of azithromycin whenadministered concomitantly with venetoclax.

Gastric acid reducing agents

Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pumpinhibitors, 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 reducethe 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, andvenetoclax should be administered at least 4-6 hours after the sequestrant.

Agents that may have their plasma concentrations altered by venetoclax

In a drug-drug interaction study in three healthy volunteers, administration of a single dose of 400 mgvenetoclax 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 internationalnormalized 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 ina 35% increase in digoxin Cmax and a 9% increase in digoxin AUC. Co-administration of narrowtherapeutic index P-gp, or BCRP substrates (e.g., digoxin, dabigatran, everolimus, sirolimus) withvenetoclax 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 asmuch as possible to minimise a potential interaction.

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

Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after endingtreatment. Therefore, women of childbearing potential must use highly effective contraceptivemeasures while taking venetoclax and for 30 days after stopping treatment. It is currently unknownwhether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore womenusing hormonal contraceptives should add a barrier method.

Based on embryo-foetal toxicity studies in animals (see section 5.3), venetoclax may harm the foetuswhen administered to pregnant women.

There are no adequate and well-controlled data from the use of venetoclax in pregnant women. Studiesin animals have shown reproductive toxicity (see section 5.3). Venetoclax is not recommended duringpregnancy and in women of childbearing potential not using highly effective contraception.

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.

No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity indogs 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 somemale patients.

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

Chronic lymphocytic leukaemia

The overall safety profile of Venclyxto is based on data from 758 patients with CLL treated in clinicalstudies with venetoclax in combination with obinutuzumab or rituximab or as monotherapy. Thesafety analysis included patients from two phase 3 studies (CLL14 and MURANO), two phase 2studies (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 receivedvenetoclax in combination with obinutuzumab. MURANO was a randomised, controlled study inwhich 194 patients with previously treated CLL received venetoclax in combination with rituximab. Inthe phase 2 and phase 1 studies, 352 patients with previously treated CLL, which included 212 patientswith 17p deletion and 146 patients who had failed a B-cell receptor pathway inhibitor were treatedwith venetoclax monotherapy (see section 5.1).

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

The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax incombination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS.

In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) werepneumonia and febrile neutropenia.

Acute myeloid leukaemia

The overall safety profile of Venclyxto is based on data from 314 patients with newly diagnosed acutemyeloid leukaemia (AML) treated in clinical studies with venetoclax in combination with ahypomethylating agent (azacitidine or decitabine) (VIALE-A phase 3 randomised, and M14-358 phase1 non-randomised).

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

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax incombination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage.

In the M14-358 study, the most commonly occurring adverse reactions (≥20%) of any grade inpatients receiving venetoclax in combination with decitabine were thrombocytopenia, febrileneutropenia, 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 combinationwith azacitidine and 6.3% (9/144) in the placebo with azacitidine arm.

The 30-day mortality rate in the M14-358 study with venetoclax in combination with decitabine was6.5% (2/31).

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 fromavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing 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 venetoclaxa a

System organ class Frequency All grades Grade ≥3

Very common Upper respiratory tractinfection

Infections and

Sepsisinfestations Sepsis

Common Urinary tract infection

Upper respiratory tract infection

Very common Anaemia

Blood and lymphatic Lymphopeniasystem disorders

Common Febrile neutropenia

Lymphopenia

Very common Hyperphosphataemia

Metabolism and

Tumour lysis syndromenutrition disorders

Tumour lysis syndrome Hyperkalaemia

Common Hyperuricaemia Hyperphosphataemia

Hyperuricaemia

Very common

Nausea

Gastrointestinal Diarrhoeadisorders Common Vomiting

Nausea

Uncommon Constipation

General disorders Very common Fatigueand administrationsite conditions

Common Fatigue

Blood creatinine

Investigations Commonincreased

Uncommon Blood creatinine increasedaOnly the highest frequency observed in the studies 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 hypomethylatingagent in patients with AML are summarised in Table 9.

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

System organ class Frequency All grades Grade ≥3

Pneumoniab Pneumoniab

Infections and Very common Sepsisb Sepsisbinfestations Urinary tract infection

Common Urinary tract infection

Neutropeniab Neutropeniab

Blood and lymphatic Febrile neutropenia Febrile neutropenia

Very commonsystem disorders Anaemiab Anaemiab

Thrombocytopeniab Thrombocytopeniab

Very common Hypokalaemia

Decreased appetite

Metabolism andnutrition disorders Common Tumour lysis syndrome Decreased appetite

Uncommon Tumour lysis syndrome

Dizziness/syncopeb

Very common

Nervous System

Common Dizziness/syncopeb

Disorders

Uncommon Headache

Very common Haemorrhageb

Haemorrhageb

Vascular Disorders

Common Hypotension

Respiratory, Very common Dyspnoeathoracic, andmediastinal disorder Common Dyspnoea

Nausea

Very common Vomiting

Stomatitis

Gastrointestinal Abdominal paindisorders Nausea

Common Diarrhoea

Uncommon Stomatitis

Hepatobiliary

Common Cholecystitis/cholelithiasisb Cholecystitis/cholelithiasisb

Disorders

Musculoskeletal

Very common Arthralgiadisorders andconnective tissuedisorders Uncommon Arthralgia

General disorders Fatigue

Very commonand administration Astheniasite conditions Fatigue

Common

Asthenia

Weight decreased

Very common

Investigations Blood bilirubin increased

Weight decreased

Common

Blood bilirubin increasedaOnly the highest frequency observed in the studies is reported (based on studies VIALE-A and M14-358).

bIncludes multiple adverse reaction terms.

Discontinuation and dose reductions due to adverse reactions

Chronic lymphocytic leukaemia

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax incombination with obinutuzumab or rituximab in the CLL14 and MURANO studies, respectively. Inthe 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 combinationof venetoclax and obinutuzumab in the CLL14 study, in 15% of patients treated with the combinationof venetoclax and rituximab in the MURANO study and in 14% of patients treated with venetoclax inthe monotherapy studies.

Dose interruptions due to adverse reactions occurred in 74% of patients treated with the combinationof venetoclax and obinutuzumab in the CLL14 study and in 71% of patients treated with thecombination of venetoclax and rituximab in the MURANO study; the most common adverse reactionthat 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 dueto adverse reactions occurred in 40% of patients; the most common adverse reaction leading to doseinterruption was neutropenia (5%).

Acute myeloid leukaemia

In the VIALE-A study, discontinuations of venetoclax due to adverse reactions occurred in 24% ofpatients treated with the combination of venetoclax and azacitidine. Venetoclax dosage reductions dueto adverse reactions occurred in 2% of patients. Venetoclax dose interruptions due to adverse reactionsoccurred 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 todose interruption (>10%) of venetoclax were febrile neutropenia, neutropenia, pneumonia, andthrombocytopenia.

In the M14-358 study, discontinuations due to adverse reactions occurred in 26% of patients treatedwith the combination of venetoclax and decitabine. Dosage reductions due to adverse reactionsoccurred 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 febrileneutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and whiteblood cell count decreased.

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 higherstarting dose, the incidence of TLS was 13% (10/77; 5 laboratory TLS; 5 clinical TLS), including 2fatal 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 andmonitoring measures. In venetoclax clinical studies, patients with any measurable lymph node ≥10 cmor those with both an ALC ≥25 x 109/l and any measurable lymph node ≥5 cm were hospitalised toenable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg duringthe 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 dailydose 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; orwere 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) inpatients treated with venetoclax + rituximab. After 77/389 patients were enrolled in the study, theprotocol was amended to incorporate the current TLS prophylaxis and monitoring measures describedin “Posology” (see section 4.2). All events of TLS occurred during the venetoclax dose-titration phaseand resolved within two days. All six patients completed the dose-titration and reached therecommended daily dose of 400 mg of venetoclax. No clinical TLS was observed in patients whofollowed 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 hyperkalaemia1%, hyperphosphataemia 1%, and hyperuricaemia 1%.

In the open-label, randomised phase 3 study (CLL14), the incidence of TLS was 1.4% (3/212) inpatients treated with venetoclax + obinutuzumab. All three events of TLS resolved and did not lead towithdrawal 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 single20 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 theincidence of TLS was 1.1% (3/283, 1 clinical TLS). The study required reduction of white blood cellcount to <25 x 109/l prior to venetoclax initiation and a dose-titration schedule in addition to standardprophylaxis and monitoring measures (see section 4.2). All cases of TLS occurred duringdose-titration.

In M14-358 study, no events of laboratory or clinical TLS were reported with venetoclax incombination 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 thevenetoclax + obinutuzumab arm; 41% of patients treated with venetoclax + obinutuzumab experienceddose interruption and 2% of patients discontinued venetoclax due to neutropenia. Grade 3 neutropeniawas reported in 25% of patients and grade 4 neutropenia in 28% of patients. The median duration ofgrade 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 toinfection occurred in 1.9% of patients while on treatment and 1.9% of patients following treatmentdiscontinuation.

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

Acute myeloid leukaemia

In the VIALE-A study, grade ≥3 neutropenia was reported in 45% of patients. The following were alsoreported in the venetoclax + azacitidine arm versus the placebo + azacitidine arm, respectively: febrileneutropenia 42% versus 19%, grade ≥3 infections 64% versus 51%, and serious infections 57% versus44%.

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

The safety profile of venetoclax in paediatric patients is based on data from an open-label phase 1study (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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for venetoclax. Patients who experience overdose should be closelymonitored and appropriate supportive treatment provided. During dose-titration phase, treatmentshould 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 orcloudy urine, unusual tiredness, muscle or joint pain, abdominal pain, and distension) along with othertoxicities (see section 4.2). Based on venetoclax large volume of distribution and extensive proteinbinding, dialysis is unlikely to result in significant removal of venetoclax.

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

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 tumourcell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directlyto 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, andprogrammed cell death. In non-clinical studies, venetoclax has demonstrated cytotoxic activity intumour cells that overexpress BCL-2.

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

Chronic lymphocytic leukaemia

Venetoclax in combination with obinutuzumab for the treatment of patients with previously untreated

CLL - study BO25323 (CLL14)

A randomised (1:1), multicentre, open-label phase 3 study evaluated the efficacy and safety ofvenetoclax + 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 prophylaxisaccordingly 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, then1000 mg doses on Days 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle, for a total of 6cycles. On Day 22 of Cycle 1, patients in the venetoclax + obinutuzumab arm began the 5-weekvenetoclax 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 lastday of Cycle 12. Each cycle was 28 days. Patients randomised to the obinutuzumab + chlorambucilarm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1-12. Patients continued tobe followed for disease progression and overall survival (OS) after completing therapy.

Baseline demographic and disease characteristics were similar between the study arms. The medianage 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% ofpatients 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 primaryanalysis was 28 months (range: 0 to 36 months).

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

Progression-free survival (PFS) was assessed by investigators using the International Workshop for

Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working

Group (NCI-WG) guidelines (2008).

At the time of the primary analysis (data cut-off date 17 August 2018), 14% (30/216) of patients in thevenetoclax + obinutuzumab arm had a PFS event of disease progression or death compared with 36%(77/216) in the obinutuzumab + chlorambucil arm, as assessed by investigators (hazard ratio [HR]:

0.35 [95% confidence interval [CI]: 0.23, 0.53]; p<0.0001, stratified log-rank test). Median PFS wasnot reached in either study arm.

Progression-free-survival was also assessed by an Independent Review Committee (IRC) and wasconsistent with the investigator-assessed PFS.

Investigator-assessed overall response rate (ORR) was 85% (95% CI: 79.2, 89.2) and 71% (95% CI:

64.8, 77.2) in the venetoclax + obinutuzumab and obinutuzumab + chlorambucil arms, respectively(p=0.0007, Cochran-Mantel-Haenszel test). Investigator-assessed complete remission + completeremission with incomplete marrow recovery (CR + CRi) rate was 50% and 23% in thevenetoclax + obinutuzumab and obinutuzumab + chlorambucil arms, respectively (p<0.0001,

Cochran-Mantel-Haenszel test).

Minimal residual disease (MRD) at the end of treatment was evaluated using allele-specificoligonucleotide polymerase chain reaction (ASO-PCR) assay. MRD negativity was defined as lessthan one CLL cell per 104 leukocytes. MRD negativity rates in peripheral blood were 76% (95% CI:69.2, 81.1) in the venetoclax + obinutuzumab arm compared to 35% (95% CI: 28.8, 42.0) in theobinutuzumab + chlorambucil arm (p<0.0001). Per protocol, MRD in bone marrow was to be assessedonly in responding patients (CR/CRi and partial remission [PR]). MRD negativity rates in the bonemarrow were 57% (95% CI: 50.1, 63.6) in the venetoclax + obinutuzumab arm and 17% (95% CI:12.4, 22.8) in the obinutuzumab + chlorambucil arm (p<0.0001).

65-month follow-up

Efficacy was assessed after a median follow-up of 65 months (data cut-off date 8 November 2021).

Efficacy results for the CLL14 65-month follow-up are presented in Table 10. The Kaplan-Meiercurve of investigator-assessed PFS is shown in Figure 1.

Table 10: Investigator-assessed efficacy results in CLL14 (65-month follow-up)

Endpoint Venetoclax + Obinutuzumab +obinutuzumab chlorambucil

N = 216 N = 216

Progression-free survival

Number of events (%) 80 (37) 150 (69)

Median, months (95% CI) NR (64.8, NE) 36.4 (34.1, 41.0)

Hazard ratio, stratified (95% CI) 0.35 (0.26, 0.46)

Overall survival

Number of events (%) 40 (19) 57 (26)

Hazard ratio, stratified (95% CI) 0.72 (0.48, 1.09)

CI= confidence interval; NE = not evaluable; NR = not reached

Figure 1: Kaplan-Meier curve of investigator-assessed progression-free survival (intent-to-treatpopulation) in CLL14 with 65-month follow-up80 -60 -20 -

Obinutuzumab + Chlorambucil (N=216)

- *-*—*—* Venetoclax + Obinutuzumab (N=216)0- + Censored

No. of Patients at Riskosinusuumas+ Chlerantue0 216 202 195 191 185 167 154 142 130 124 118 115 101 94 75 72 64 62 53 50 39 33 21 17 1

Venetoc + okinuturlimau 216 200 196 195 192 188 183 180 177 174 169 165 160 157 147 143 134 129 123 118 97 78 35 24 41 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75

Time (month)

The PFS benefit with venetoclax + obinutuzumab versus obinutuzumab + chlorambucil treatment wasobserved across all subgroups of patients evaluated, including high-risk patients with deletion 17pand/or TP53 mutation and/or unmutated IgVH.

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

A randomised (1:1), multicentre, open-label phase 3 study evaluated the efficacy and safety ofvenetoclax + rituximab versus bendamustine + rituximab in patients with previously treated CLL.

Patients in the venetoclax + rituximab arm completed the Venclyxto 5-week dose-titration scheduleand then received 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence ofdisease progression or unacceptable toxicity. Rituximab was initiated after the 5-week dose-titrationschedule at 375 mg/m2 for Cycle 1 and 500 mg/m2 for Cycles 2-6. Each cycle was 28 days. Patientsrandomised to bendamustine + rituximab received bendamustine at 70 mg/m2 on Days 1 and 2 for 6cycles and rituximab as described above.

Median age was 65 years (range: 22 to 85); 74% were male, and 97% were white. Median time sincediagnosis was 6.7 years (range: 0.3 to 29.5). Median prior lines of therapy was 1 (range: 1 to 5); andincluded alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors(2%) and prior purine analogues (81%, including 55% fludarabine + cyclophosphamide + rituximab(FCR)). At baseline, 47% of patients had one or more nodes ≥5 cm, and 68% had ALC ≥25 x 109/l. A17p deletion was detected in 27% of patients, TP53 mutations in 26%, 11q deletion in 37%, andunmutated 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 was assessed by investigators using the IWCLL updated NCI-WG guidelines(2008).

At the time of the primary analysis (data cut-off date 8 May 2017), 16% (32/194) of patients in thevenetoclax + rituximab arm had experienced a PFS event, compared with 58% (114/195) in thebendamustine + rituximab arm (HR: 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

Progression-Free Survivalwas not reached in the venetoclax + rituximab arm and was 17.0 months (95% CI: 15.5, 21.6) in thebendamustine + 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) inthe venetoclax + rituximab arm and 73% (95% CI: 65.9, 79.1) and 36% (95% CI: 28.5, 44.0) in thebendamustine + rituximab arm, respectively.

Efficacy results for the primary analysis were also assessed by an IRC demonstrating a statisticallysignificant 81% reduction in the risk of progression or death for patients treated with venetoclax +rituximab (HR: 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%, nodular partial remission (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 duration of response (DOR) was notreached with median follow-up of approximately 23.8 months. The IRC-assessed ORR for patientstreated with venetoclax + rituximab was 92% (95% CI: 87.6, 95.6), with a CR + CRi rate of 8%, nPRrate 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 of68%. The discrepancy between IRC- and investigator-assessed CR rates was due to interpretation ofresidual adenopathy on CT scans. Eighteen patients in the venetoclax + rituximab arm and 3 patientsin the bendamustine + rituximab arm had negative bone marrow and lymph nodes <2 cm.

MRD at the end of combination treatment was evaluated using ASO-PCR and/or flow cytometry.

MRD negativity was defined as less than one CLL cell per 104 leukocytes. MRD negativity rates inperipheral 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 availablein peripheral blood, 72% (121/167) in the venetoclax + rituximab arm and 20% (26/128) in thebendamustine + rituximab arm were found to be MRD negative. MRD negativity rates in the bonemarrow 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 armwere found to be MRD negative.

Median OS had not been reached in either treatment arm. Death occurred in 8% (15/194) of patientstreated 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 treatmentor 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). Efficacyresults for the MURANO 59-month follow-up are presented in Table 11.

Table 11: Investigator-assessed efficacy results in MURANO (59-month follow-up)

Endpoint Venetoclax + Bendamustine +rituximab rituximab

N = 194 N = 195

Progression-free survival

Number of events (%)a 101 (52) 167 (86)

Median, months (95% CI) 54 (48.4, 57.0) 17 (15.5, 21.7)

Hazard ratio, stratified (95% CI) 0.19 (0.15, 0.26)

Overall survival

Number of events (%) 32 (16) 64 (33)

Hazard ratio (95% CI) 0.40 (0.26, 0.62)60-month estimate, % (95% CI) 82 (76.4, 87.8) 62 (54.8, 69.6)

Time to next anti-leukaemic treatment

Number of events (%)b 89 (46) 149 (76)

Median, months (95% CI) 58 (55.1, NE) 24 (20.7, 29.5)

Hazard ratio, stratified (95% CI) 0.26 (0.20, 0.35)

MRD negativitycf

Peripheral blood at end of treatment, n (%)d 83 (64) NA3-year PFS estimate from end of treatment, % (95% CI)e 61 (47.3, 75.2) NAf3-year OS estimate from end of treatment, % (95% CI)e 95 (90.0, 100.0) NAf

CI= confidence interval; MRD = minimal residual disease; NE = not evaluable; OS= overall survival;

PFS = progression-free survival; NA = not applicable.a87 and 14 events in the venetoclax + rituximab arm were due to disease p rogression and death, comparedto 148 and 19 events in the bendamustine + rituximab arm, respectively.b68 and 21 events in the venetoclax + rituximab arm were due to patients starting a new anti-leukaemictreatment and death, compared to 123 and 26 events in the bendamustine + rituximab arm, respectively.cMinimal residual disease was evaluated using allele-specific oligonucleotide polymerase chain reaction(ASO-PCR) and/or flow cytometry. The cut-off for a negative status was one CLL cell per 104leukocytes.dIn patients who completed venetoclax treatment without progression (130 patients).eIn patients who completed venetoclax treatment without progression and were MRD negative (83patients).fNo equivalent to end of treatment visit in bendamustine + rituximab arm.

In total, 130 patients in the venetoclax + rituximab arm completed 2 years of venetoclax treatmentwithout 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-treatpopulation) in MURANO (data cut-off date 8 May 2020) with 59-month follow-up

Bendamustine+Rituximab (N=195)— * — - Venclyxto+Rituximab (N=194)

Censored

No. of Patients at RiSk

Boodarnolne.14444.811 195 178 165 143 1213 103 SA 79 65 55 44 39 31 24 21 18 11 10 2 1

V4otlig641.444,466 194 1SO 165 179 176 174 170 167 161 IS0 142 135 132 123 116 101 99 87 57 33 15 10 3 20 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

Time (month)

Results of subgroup analyses

The observed PFS benefit of venetoclax + rituximab compared with bendamustine + rituximab wasconsistently observed across all subgroups of patients evaluated, including high-risk patients withdeletion 17p/TP53 mutation and/or unmutated IgVH (Figure 3).

Figure 3: Forest plot of investigator-assessed progression-free survival in subgroups from MURANO(data cut-off date 8 May 2020) with 59-month follow-up

Bendamustine+ Venetoclax+

Rituximab Rituximab(N=195) (N=194) Venetoclax+ Bendamustine+

Total Median Median Hazard 95% Wald Rituximab Rituximab

Su rou s n n (Months) n (Months) Ratio CI better better

AJI Patients 389 195 17.0 194 53.6 0.21 (0.16. 0.27)

Chromosome 17p Deletion (central)

Normal 250 123 21.6 127 55.1 0.19

Abnormal 92 46 14.6 46 47.9 0.27 ig:1g : 8:gp53 Mutation and/or 17p Deletion (central)

Unmutated 201 95 22.9 106 56.6 0.18

Mutated 147 75 14.2 72 45.3 0.26 ig:13: SA

Age Group 65 (yr)< 65 186 89 15.4 97 49.0 0.20 0.29)>= 65 203 106 21.7 97 57.0 0.20 il3:1::

Age Group 75 (yr)< 75 336 171 16.4 165 53.5 0.21>= 75 53 24 20.0 29 64.5 0.24 ig:1 : SR

Number of Prior Regimens1 228 117 16.4 111 54.0 0.18> 1 161 78 18.6 83 53.1 0.25 ig:13: 8:0

Bulky Disease (Lymph Nodes with the Largest Diameter)< 5 cm 197 97 16.6 100 53.8 0.21 0.30)>= 5 cm 172 88 15.8 84 48.4 0.19 all:

Baseline IgVH Mutation Status

Mutated 104 51 24.2 53 NE 0.14

Unmutated 246 123 15.7 123 52.2 0.19 igE: SA

Refractory vs. Relapse to Most Recent Prior Therapy

Refractory 59 29 13.6 30 31.9 0.34

Relapse 330 166 18.6 164 53.8 0.19 ig:174: 8:M1/100 10017p 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.

Final overall survival analysis (86-month follow-up)

At the time of the final OS analysis (data cut-off date 03 August 2022), a total of 144 randomisedpatients had died; 60/194 patients (31%) in the venetoclax + rituximab arm and 84/195 patients (43%)in the bendamustine + rituximab arm. The median OS was not reached in the venetoclax + rituximabarm and was 88 months in the bendamustine + rituximab arm. The estimated risk of death wasdecreased by 47% for patients treated with venetoclax + rituximab (stratified HR = 0.53; 95% CI:

0.37, 0.74). The final OS analysis was not type I error controlled. The Kaplan-Meier curve of overallsurvival is shown in Figure 4.

Figure 4: Kaplan-Meier curve of overall survival (intent-to-treat population) in MURANO (data cut-off date 03 August 2022) with 86-month follow-up100 -

*80 - ' *'4- '*+*20 -

Bendamustine+Rituximab (N=195)

Venetoclax+Rituximab (N=194)0 - -I- Censored

No. of Patients at Risk

Bendamustme*Ritummab 195 181 175 167 162 155 152 150 147 141 140 138 134 131 124 121 115 110 107 103 102 99 97 94 88 86 83 78 55 35 17 3

Venetoclax*Rtummab 194 190 185 183 182 179 178 176 173 168 166 165 164 163 161 160 159 158 156 153 151 150 149 147 141 136 131 125 82 53 19 11 4g g g g g g g g i g g0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time (month)

Venetoclax as monotherapy for the treatment of patients with CLL harbouring 17p deletion or TP53mutation - study M13-982

The safety and efficacy of venetoclax in 107 patients with previously treated CLL with 17p deletionwere evaluated in a single-arm, open-label, multicentre study (M13-982). Patients followed a 4- to5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally400 mg once daily. Patients continued to receive venetoclax 400 mg once daily until diseaseprogression or unacceptable toxicity was observed. The median age was 67 years (range: 37 to85 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 to10 treatments); 49.5% with a prior nucleoside analogue, 38% with prior rituximab, and 94% with aprior alkylator (including 33% with prior bendamustine). At baseline, 53% of patients had one or morenodes ≥5 cm, and 51% had ALC ≥25 x 109/l. 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 mediantime on treatment at the time of evaluation was 12 months (range: 0 to 22 months).

The primary efficacy endpoint was ORR as assessed by an IRC using the IWCLL updated NCI-WGguidelines (2008). Efficacy results are shown in Table 12. Efficacy data are presented for 107 patientswith data cut-off date 30 April 2015. An additional 51 patients were enrolled in a safety expansioncohort. Investigator-assessed efficacy results are presented for 158 patients with a later data cut-offdate 10 June 2016. The median time on treatment for 158 patients was 17 months (range: 0 to34 months).

Table 12: Efficacy results in patients with previously treated CLL with 17p deletion (study M13-982)

Endpoint IRC assessment Investigator assessmenta b(N = 107) (N = 158)

Data cutoff date 30 April 2015 10 June 2016

ORR, % 79 77(95% CI) (70.5, 86.6) (69.9, 83.5)

CR + CRi, % 7 18nPR, % 3 6

PR, % 69 53

DOR, months, median (95% CI) NR 27.5 (26.5, NR)

PFS, % (95% CI)12-month estimate 72 (61.8, 79.8) 77 (69.1, 82.6)24-month estimate NA 52 (43, 61)

PFS, months, median NR 27.2 (21.9, NR)(95% CI)

TTR, months, median (range) 0.8 (0.1-8.1) 1.0 (0.5-4.4)aOne patient did not harbour the 17p deletion.bIncludes 51 additional patients from the safety expansion cohort.

CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrowrecovery; DOR = duration of response; IRC = independent review committee; nPR = nodular PR; NA =not available; NR = not reached; ORR = overall response rate; PFS = progression-free survival, PR =partial remission; TTR = time to first response.

Minimal residual disease (MRD) was evaluated using flow cytometry in 93 of 158 patients whoachieved CR, CRi, or PR with limited remaining disease with venetoclax treatment. MRD negativitywas defined as a result below 0.0001 (<1 CLL cell per 104 leukocytes in the sample). Twenty-sevenpercent (42/158) of patients were MRD negative in the peripheral blood, including 16 patients whowere also MRD negative in the bone marrow.

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

The efficacy and safety of venetoclax in patients with CLL who had been previously treated with andfailed ibrutinib or idelalisib therapy were evaluated in an open-label, multicentre, 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 unacceptabletoxicity was observed.

At the time of data cut-off (26 July 2017), 127 patients were enrolled and treated with venetoclax. Ofthese, 91 patients had received prior ibrutinib therapy (Arm A) and 36 had received prior idelalisibtherapy (Arm B). The median age was 66 years (range: 28 to 85 years), 70% were male, and 92% werewhite. The median time since diagnosis was 8.3 years (range: 0.3 to 18.5 years; N=96). Chromosomalaberrations 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 cmand 31% had ALC ≥25 x 109/l. 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 monoclonalantibodies, 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. Responseassessments were performed at 8 weeks, 24 weeks, and every 12 weeks thereafter.

Table 13: Efficacy results as assessed by investigator in patients who have failed a B-cell receptorpathway inhibitor (study M14-032)

Endpoint Arm A Arm B Total(ibrutinib failures) (idelalisib failures) (N = 127)(N = 91) (N = 36)

ORR, % 65 67 65(95% CI) (54.1, 74.6) (49.0, 81.4) (56.4, 73.6)

CR + CRi, % 10 11 10nPR, % 3 0 2

PR, % 52 56 53

PFS, % (95% CI)12-month estimate 75 (64.7, 83.2) 80 (63.1, 90.1) 77 (68.1, 83.4)24-month estimate 51 (36.3, 63.9) 61 (39.6, 77.4) 54 (41.8, 64.6)

PFS, months, median 25 (19.2, NR) NR (16.4, NR) 25 (19.6, NR)(95% CI)

OS, % (95% CI)12-month estimate 91 (82.8, 95.4) 94.2 (78.6, 98.5) 92 (85.6, 95.6)

TTR, months, median 2.5 (1.6-14.9) 2.5 (1.6-8.1) 2.5 (1.6-14.9)(range)17p deletion and/or TP53 mutation status

ORR, % (95% CI)

Yes (n=28) (n=7) (n=35)61 (45.4, 74.9) 58 (27.7, 84.8) 60 (46.6, 73.0)

No (n=31) (n=17) (n=48)69 (53.4, 81.8) 71 (48.9, 87.4) 70 (57.3, 80.1)

CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrowrecovery; nPR = nodular PR; NR = not reached, ORR = overall response rate; OS = overall survival; PFS =progression-free survival, PR = partial remission, TTR = time to first response.

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 CRi. The ORR for patients with 17pdeletion 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 8patients 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 thatprecluded 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 orpulmonary comorbidity, moderate hepatic impairment, creatinine clearance (CrCl) < 45 ml/min, orother 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 theefficacy 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 doseduring the first 28-day cycle of treatment (see section 4.2) and received venetoclax 400 mg orally oncedaily thereafter in subsequent cycles. Azacitidine at 75 mg/m2 was administered either intravenously orsubcutaneously 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 marrowassessment confirmed a remission, defined as less than 5% leukaemia blasts with grade 4 cytopeniafollowing 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 theend of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinicallyindicated. 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 study for management ofhematologic toxicity (see azacitidine Summary of Product Characteristics). Patients continued toreceive treatment cycles until disease progression or unacceptable toxicity.

A total of 431 patients were randomised: 286 to the venetoclax + azacitidine arm and 145 to theplacebo + azacitidine arm. Baseline demographic and disease characteristics were similar between thevenetoclax + 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 or1 for 55% of patients, 2 for 40% of patients, and 3 for 5% of patients. There were 75% of patients withde novo AML and 25% with secondary AML. At baseline, 29% of patients had bone marrow blastcount <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. Thefollowing mutations were identified: TP53 mutations in 21% (52/249), IDH1 and/or IDH2 mutation in24% (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 ofrandomisation to death from any cause and composite CR rate (complete remission + completeremission with incomplete blood count recovery [CR+CRi]). The overall median follow-up at the timeof analysis was 20.5 months (range: <0.1 to 30.7 months).

Venetoclax + azacitidine demonstrated a 34% reduction in the risk of death compared withplacebo + azacitidine (p <0.001). Results are shown in Table 14.

Table 14: Efficacy results in VIALE-A

Endpoint Venetoclax + azacitidine Placebo + azacitidine

Overall survivala (N=286) (N=145)

Number of events n (%) 161 (56) 109 (75)

Median survival, months 14.7 9.6(95% CI) (11.9, 18.7) (7.4, 12.7)

Hazard ratiob 0.66(95% CI) (0.52, 0.85)p-valueb <0.001

CR+CRi ratec (N=147) (N=79)n (%) 96 (65) 20 (25)(95% CI) (57, 73) (16, 36)p-valued <0.001

CI = confidence interval; CR = (complete remission) was defined as absolute neutrophil count>1,000/microlitre, platelets >100,000/microlitre, red blood cell transfusion independence, and bonemarrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence ofextramedullary disease; CRi = complete remission with incomplete blood count recovery.aKaplan-Meier estimate at the second interim analysis (data cut-off date 4 January 2020).bHazard ratio estimate (venetoclax +azacitidine vs. placebo + azacitidine) is based on Cox-proportional hazards model stratified by cytogenetics (intermediate risk, poor risk) and age (18to<75, ≥75) as assigned at randomisation; p-value based on log-rank test stratified by the samefactors.cThe CR+CRi rate is from a planned interim analysis of first 226 patients randomised with 6 monthsof follow-up at the first interim analysis (data cut-off date 1 October 2018).dP-value is from Cochran-Mantel-Haenszel test stratified by age (18 to <75, ≥75) and cytogeneticrisk (intermediate risk, poor risk) as assigned at randomisation.

Figure 5: Kaplan-Meier curve for overall survival in VIALE-A1.00.90.80.70.60.50.40.30.20.1

PBO+AZA VEN+AZA0.0

Number at Risk

PBO+AZA — 145 109 92 74 59 38 30 14 5

VEN+AZA — 286 219 198 168 143 117 101 54 23 50 3 6 9 12 IS 18 21 24 27 30 33

TIME (MONTH)

Key secondary efficacy endpoints are presented in Table 15.

Table 15: Additional efficacy endpoints in VIALE-A

Endpoint Venetoclax + azacitidine Placebo + azacitidine

N=286 N=145

CR raten (%) 105 (37) 26 (18)(95% CI) (31, 43) (12, 25)p-valuea <0.001

Median DORb, months 17.5 13.3(95% CI) (15.3, -) (8.5, 17.6)

CR+CRi raten (%) 190 (66) 41(28)(95% CI) (61, 72) (21, 36)

Median DORb, months 17.5 13.4(95% CI) (13.6, -) (5.8, 15.5)

PROBABILITY OF 110 EVEHT

CR+CRi rate by initiation of

Cycle 2, n (%) 124 (43) 11 (8)(95% CI) (38, 49) (4, 13)p-valuea <0.001

Transfusion independence rate,plateletsn (%) 196 (69) 72 (50)(95% CI) (63, 74) (41, 58)p-valuea <0.001

Transfusion independence rate,red blood cellsn (%) 171 (60) 51 (35)(95% CI) (54, 66) (27, 44)p-valuea <0.001

CR+CRi MRD response ratedn (% ) 67 (23) 11 (8)(95% CI) (19, 29) (4, 13)p-valuea <0.001

Event-free survival

Number of events, n (%) 191 (67) 122 (84)

Median EFSe, months 9.8 7.0(95% CI) (8.4, 11.8) (5.6, 9.5)

Hazard ratio (95% CI)c 0.63 (0.50, 0.80)p-valuec <0.001

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) withno 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 therapywhichever is earlier.

aP-value is from Cochran-Mantel-Haenszel test stratified by age (18 to <75, ≥75) and cytogeneticrisk (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, fromfirst response of CR or CRi for DOR of CR+CRi, to the first date of confirmed morphologicrelapse, confirmed progressive disease or death due to disease progression, whichever occurredearlier. Median DOR is from Kaplan-Meier estimate.cHazard ratio estimate (venetoclax + azacitidine vs. placebo + azacitidine) is based on Cox-proportional 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 samefactors.d CR+CRi MRD response rate is defined as the % of patients achieving a CR or CRi anddemonstrated 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]) and11% (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 withvenetoclax + azacitidine, 49% (71/144) became transfusion independent. Of the patients who wereplatelet 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) withvenetoclax + 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

Rambo +Ilan* Yowled= +472/anne14R (95% CO

Median MS= Verebcka * MadelinenN (%) (Ikals) (%) (Italie) es. Placebo +Azacilidne

AI Subjects 109/145 ( 752) 9.0 1811286(503) 14.7 I-M-I 0.64(059 022 )

Age (Years)18 - < 65 3/ 5 (600) 13.2 7110( 70.0) 152 1 0.95(024. 3.89)65 -< 75 33/53(623) 15.2 59/102 (57.8) 152 028(0.57. 135)75 73187 (83A) 85 95/174(54.6) 14.1 i-0-i 0.54(0.39. 0.73)

Bastin ECOG

Crack < 2 05181(802) 10.6 89/157 (56.7) 102 Fel 0.61 (044. 024)

Grack 2 44/64(68S) 8.6 72/129 ( 552) 13.3 (-0--T 0.70(048. 1.03)

Type of Mt

De Woo 80/110( 72.7) 9.6 128214(56.1) 14.1 1-0-1 0.67(0.51. 090 )

Seconlwy 29135( 829) 10.6 41/72 (83.9) 16.4 s-0-1 0458(035, 091 )

Therapyableed 8/ 9 ( 380) 11.3 15126(57.7) 16 4 0.65(0.29 1.32)

Cyr:immix Riskrternioat 62/891297) 12.4 84/182(462) 20.8 i-0-I 0.57(0.41. 0.79)

Poor 47/56(83.9) 0.0 77/104( 74.0) 7.6 0.78(0M. 1.12)

Molecular Marker by Central Lab

FLT3 19/22(86.4) 8.6 19129(265) 12.7 1-10—r1 000(038 126)0-(1.2 24/28 (85.7) 62 29/61 (47.5) e-0-4 0.341020, OM)7PS3 13/14 (924) 54 34138(895) 58 )-0-r4 0.76(0.40. 1.45)14'141 14/17( 82.4) 130 1827(59.3) 15.0 0.73(0.36. 1.51 )

Mt with Myelotlysplasia

Ralaind Changes INAL4ARCI

Yes 3.,49(ne) 11.3 56/92 (cam 12.7 0.73(0.48. 1.11)

No 71/93(740) 8.5 1051194(54.1) 10.4 0.02 (0.45 023 )

Bone Maras Bbst Gaunt< 30% 28/41 (68.3) 12.4 45,85 (54.1) 148 0.72 (0.45. 1.15)30 -c 50% 26133( 78.8) 9.3 (50.0) 188 1—M-1( 0.57 (0.24. 0.95 )50% 55171 (77.5) 8.4 70140 (50.4) 12.4 ttyi 0.03 ( 0.45, 089)

Faces WHAM l Faces PI304AZA0.1 1 10

- = 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 newlydiagnosed AML - M14-358

Study M14-358 was a non-randomised phase 1/2 clinical study of venetoclax in combination withazacitidine (n=84) or decitabine (n=31) in patients with newly diagnosed AML who were ineligible forintensive chemotherapy. Patients received venetoclax via a daily titration to a final 400 mg once dailydose. 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 beginningon 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.

Of the 194 patients with previously treated CLL who received venetoclax in combination withrituximab, 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 studies, 57% were 65 years orolder.

Of the 283 patients with newly diagnosed AML treated in the VIALE-A (venetoclax + azacitidinearm) clinical study, 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 clinicalstudy, 100% were ≥65 years of age and 26% were ≥75 years of age.

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

The safety, efficacy, and pharmacokinetics of venetoclax were evaluated in a two-part, multi-centre,open-label, phase 1 study (M13-833) of venetoclax as monotherapy or in combination withchemotherapy in 140 paediatric and young adult patients with relapsed or refractory malignancies.

Patients received venetoclax, alone or in combination with chemotherapy, at an age- or weight-adjusted dose to match an adult equivalent target dose of 400 mg or 800 mg daily or intermittently(days 1-10) for 21-day cycles.

Part 1 enrolled 22 patients in a dose determination cohort (AML (n=10), acute lymphoblasticleukaemia [ALL] (n=5), neuroblastoma (n=3), and solid tumours (n=4)) and 18 patients in a doseescalation/de-escalation cohort (neuroblastoma (n=7) and solid tumours (n=11)).

Part 2 of the study enrolled 100 patients with the following: AML (n=27), ALL (n=26), non-Hodgkinlymphoma [NHL] (n=2), neuroblastoma (n=26), and an exploratory cohort of other tumours with

BCL-2 expression or transcription factor 3-hepatic leukaemia factor ALL (n=19; solid tumours n=8and other tumours n=11). Overall, across Part 1 and 2, the median age of patients was 6 years (range:0-17 years) for patients with AML, 9 years (range: 0-25 years) for patients with ALL, 12 years (range:

3-21 years) for patients with NHL, 8 years (range: 1-17 years) for patients with neuroblastoma, 16years (range: 3-24 years) for patients with solid tumours, and 10 years (range: 5-19 years) for patientswith other tumours.

Efficacy analyses included patients from Part 1 and Part 2 (n=129), and excluded patients from theexploratory other tumours cohort. The ORR was 24% and the CR rate was 16% in the AML cohort,with an estimated median DOR of 2.6 months (95% CI: 0.5, 7.9). The ORR was 42% (all CR) in the

ALL cohort, with an estimated median DOR of 10.2 months (95% CI: 2.8, 14.2). One of the twopatients in the NHL cohort achieved a partial response; the DOR was 1.4 months. Median DOR wasnot estimable, and meaningful conclusions are limited due to the small sample size. The ORR was31% and the CR rate was 22% in the neuroblastoma cohort, with an estimated median DOR of 9.3months (95% CI: 3.9, NE). The ORR was 22% and the CR rate was 4% in the solid tumours cohort,with an estimated median DOR of 11.1 months (95% CI: 3.1, NE).

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 the treatment of malignant neoplasmsof the haematopoetic and lymphoid tissue (see section 4.2 for information on paediatric use).

Following multiple oral administrations, maximum plasma concentration of venetoclax was reached5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of150-800 mg. Under low-fat meal conditions, venetoclax mean (± standard deviation) steady state Cmaxwas 2.1 ± 1.1 mcg /ml and AUC24 was 32.8 ± 16.9 mcg *h/ml at the 400 mg once daily dose.

Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold andadministration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared tofasting conditions. It is recommended that venetoclax should be administered with a meal (see section4.2).

Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across aconcentration range of 1-30 micromolar (0.87-26 mcg/ml). The mean blood-to-plasma ratio was 0.57.

The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from256-321 L in patients.

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 inhibitorof CYP2C8, CYP2C9 and UGT1A1 in vitro, but it is not predicted to cause clinically relevantinhibition. 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 OATP1B1inhibitor in vitro (see section 4.5). Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2,

OAT1, OAT3, MATE1, or MATE2K at clinically relevant concentrations.

The population estimate for the terminal phase elimination half-life of venetoclax was approximately26 hours. Venetoclax shows minimal accumulation with accumulation ratio of 1.30-1.44. After asingle oral administration of 200 mg radiolabeled [14C]-venetoclax to healthy subjects, >99.9% of thedose was recovered in faeces and <0.1% of the dose was excreted in urine within 9 days. Unchangedvenetoclax accounted for 20.8% of the administered radioactive dose excreted in faeces. Thepharmacokinetics of venetoclax do not change over time.

Based on pharmacokinetic analysis in paediatric patients with relapsed/refractory malignancies, theuse of weight-based dosing for patients 2 years and above would yield venetoclax plasma exposuresthat are comparable across different paediatric weight subgroups and comparable to those observed inadult patients receiving venetoclax 400 mg as shown in Table 16.

Table 16: Venetoclax exposures for paediatric weight groups in patients 2 years and above at 400 mgadult-equivalent dose

Paediatric10 - ≤ 20 kg 20 - ≤ 30 kg 30 - ≤ 45 kg ≥ 45 kg

Subgroup Adults(5) (4) (6) (13)(n)

AUC *22.4 ± 13.1 27.5 ± 27.5 38.3 ± 36.9 26.0 ± 24.3 32.8 ± 16.9(mcg*h/mL)

*Mean ± standard deviation

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 normalrenal function (CrCl ≥90 ml/min), venetoclax exposures in subjects with mild, moderate or severerenal impairment are similar to those with normal renal function. The pharmacokinetics of venetoclaxhas not been studied in subjects with CrCl <15 ml/min or patients on dialysis (see section 4.2).

Based on a population pharmacokinetic analysis that included 74 subjects with mild hepaticimpairment, 7 subjects with moderate hepatic impairment and 442 subjects with normal hepaticfunction, venetoclax exposures are similar in subjects with mild and moderate hepatic impairment andnormal hepatic function. Mild hepatic impairment was defined as normal total bilirubin and aspartatetransaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderatehepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as totalbilirubin >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 withnormal 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 withnormal 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 onvenetoclax clearance. The exposure is 67% higher in Asian subjects as compared to non-Asiansubjects. This difference is not considered clinically relevant.

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

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

After approximately 3 months of daily dosing in dogs, venetoclax caused progressive whitediscoloration 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 asingle dose level of 250 mg/kg/day of M27. Exposure margins (AUC), relative to the clinical AUC at400 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 assayand in vivo mouse micronucleus assay. The M27 metabolite was negative for genotoxicity in thebacterial mutagenicity and chromosomal aberration assays.

No effects on fertility were observed in fertility and early embryonic development studies in male andfemale mice. Testicular toxicity (germ cell loss) was observed in general toxicity studies in dogs atexposures of 0.5 to 18 times the human AUC exposure at a dose of 400 mg. Reversibility of thisfinding 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 AUCexposure 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 exposureat a 400 mg dose of venetoclax. In rabbits, venetoclax produced maternal toxicity, but no foetaltoxicity at exposures of 0.1 times the human AUC exposure at a 400 mg dose.

Venclyxto 10 mg film-coated tablets

Copovidone (K 28)

Colloidal anhydrous silica (E551)

Polysorbate 80 (E433)

Sodium stearyl fumarate

Anhydrous calcium hydrogen phosphate (E341 (ii))

Iron oxide yellow (E172)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Venclyxto 50 mg film-coated tablets

Copovidone (K 28)

Colloidal anhydrous silica (E551)

Polysorbate 80 (E433)

Sodium stearyl fumarate

Anhydrous calcium hydrogen phosphate (E341 (ii))

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Venclyxto 100 mg film-coated tablets

Copovidone (K 28)

Colloidal anhydrous silica (E551)

Polysorbate 80 (E433)

Sodium stearyl fumarate

Anhydrous calcium hydrogen phosphate (E341 (ii))

Iron oxide yellow (E172)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Not applicable.

Venclyxto 10 mg film-coated tablets2 years.

Venclyxto 50 mg film-coated tablets2 years.

Venclyxto 100 mg film-coated tablets3 years.

This medicinal product does not require any special storage conditions.

Venclyxto film-coated tablets are supplied in:

* blisters: PVC/PE/PCTFE aluminium foil blisters containing either 1, 2 or 4 film-coated tablets

* bottles: HDPE bottles with induction-sealed child resistant polypropylene cap containing 120tablets.

Venclyxto 10 mg film-coated tablets

The film-coated tablets are supplied in cartons containing either 10 or 14 tablets (in blisters of2 tablets).

Venclyxto 50 mg film-coated tablets

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

Venclyxto 100 mg film-coated tablets

The film-coated tablets are supplied in cartons:

* containing 7 (in blisters of 1 tablet) or 14 tablets (in blisters of 2 tablets); or a multipackcontaining 112 tablets (4 x 28 tablets (in blisters of 4 tablets))

* containing 360 tablets (3 bottles each with 120 tablets).

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/16/1138/001 (10 mg, 10 tablets)

EU/1/16/1138/002 (10 mg, 14 tablets)

EU/1/16/1138/003 (50 mg, 5 tablets)

EU/1/16/1138/004 (50 mg, 7 tablets)

EU/1/16/1138/005 (100 mg 7 tablets)

EU/1/16/1138/006 (100 mg, 14 tablets)

EU/1/16/1138/007 (100 mg, 112 (4 x 28) tablets)

EU/1/16/1138/008 (100 mg, 360 tablets)

Date of first authorisation: 5 December 2016

Date of latest renewal: 11 August 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.