Consumer medicine information

Venclexta

Venetoclax

BRAND INFORMATION

Brand name

Venclexta

Active ingredient

Venetoclax

Schedule

What is in this leaflet

This leaflet answers some common questions about Venclexta.

It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

Warning

Tumour Lysis Syndrome (TLS), which can be fatal, has rarely occurred in patients receiving Venclexta.

Ensure you follow your doctor's instructions carefully especially when you start treatment with Venclexta. This includes keeping all of your appointments, including blood tests set up for you each week at the start of your treatment. The changes in your blood that could lead to TLS may show no symptoms.

Tell your doctor, nurse or pharmacist if you have or have had kidney problems, as this can increase the risk of TLS.

What Venclexta is used for

Venclexta is used, in combination with rituximab or alone, to treat a condition called "Chronic Lymphocytic Leukaemia (CLL)".

CLL is a type of cancer affecting white blood cells called "B lymphocytes" and may also involve the lymph nodes, which are glands throughout the body that contain white blood cells. In CLL, the B cells multiply too quickly and live too long, so that there are too many of them in the blood.

Venclexta is used, in combination with azacitidine or with low dose cytarabine, to treat a condition called "Acute Myeloid Leukaemia (AML)". This medicine has provisional approval in Australia for AML. The decision to approve this medicine has been made on the basis of promising results from preliminary studies. More evidence is required to be submitted when available to fully confirm the benefit and safety of the medicine for this use.

AML is a type of cancer affecting cells in the blood and bone marrow called "myeloid blasts". In AML, changes in these cells prevent them from turning into mature blood cells, resulting in too many of them and too few mature blood cells, platelets and other white blood cells in the blood.

The active substance in this medicine is called venetoclax.

Venclexta works by blocking a protein in the body ("BCL-2") that helps these cancer cells survive. Blocking this protein helps to kill and reduce the number of cancer cells, and may slow the spread of the disease.

Ask your doctor, nurse or pharmacist if you have any questions about why it has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is available only with a doctor’s prescription.

Before you take Venclexta

When you must not take it

Do not take Venclexta if you have an allergy to:

any medicine containing venetoclax
any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include

hives, skin rash or itching
shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

For patients with CLL, do not take Venclexta if you are taking any medicine that contains:

ketoconazole, posaconazole, voriconazole or itraconazole, medicines used for fungal infections
clarithromycin, a medicine used to treat bacterial infections
conivaptan, a medicine used to treat low sodium levels
ritonavir, indinavir, lopinavir or telaprevir, medicines used to treat HIV or HCV (hepatitis C virus) infections.

Do not take it after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

If you use this medicine after the expiry date has passed it may not work as well.

Before you start to take it

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

heart, kidney or liver problems
an infection.

If you have not told your doctor or pharmacist about any of the above, tell them before you take Venclexta.

Tell your doctor if you recently received or are scheduled to receive a vaccine. Certain vaccines may cause infections and should not be given while taking Venclexta.

Do not take Venclexta if you are pregnant or plan to become pregnant. Venclexta should not be used during pregnancy. Your doctor may conduct a pregnancy test and discuss contraception options with you before you start taking your medicine.

Do not take Venclexta if you are breastfeeding or plan to breastfeed. It is not known whether this medicine passes into the breast milk.

Your doctor will discuss the risks and benefits of using this medicine if you are breastfeeding.

Tell your doctor or pharmacist if you have any allergies to any other medicines, foods, preservatives or dyes.

If you have not told your doctor or pharmacist about any of the above, tell them before you take Venclexta.

Use in Children

Do not give Venclexta to children and adolescents under 18 years of age. The safety and effectiveness of Venclexta in children and adolescents have not yet been established.

Tumour Lysis Syndrome

Venclexta can cause Tumour Lysis Syndrome, a very serious side effect that can be fatal.

Some people having treatment for cancer can develop Tumour Lysis Syndrome (TLS), which is caused by the fast breakdown of cancer cells. As the cancer cells are destroyed, they break open and what is inside the cancer cell (uric acid, potassium, phosphorus) gets into the blood. This can lead to changes in kidney function, sudden kidney failure or even death.

To help prevent TLS, drink 6-8 glasses (approximately 1.5 - 2 litres total) of water each day, especially starting 2 days before and on the day of your first dose of Venclexta, and every time the dose is increased. It is important that you continue to remain hydrated throughout your treatment.

Before you start your treatment, your doctor will do blood tests and a scan (for example, a CT scan) to see if you are at risk of developing TLS. It is important for you to keep your scheduled appointments for blood tests. The changes in your blood that could lead to TLS may have no symptoms.

If the following symptoms occur, contact your doctor immediately:

fever or chills
feeling or being sick (nausea or vomiting)
feeling confused
feeling short of breath
irregular heart beat
dark or cloudy urine
fits or seizures
feeling unusually tired
muscle pain or joint discomfort.

TLS is most likely to occur when you are first starting your treatment.

Follow all instructions given to you by your doctor.

Your doctor may give you medicines (such as allopurinol) to help prevent the build-up of uric acid in your body before you start treatment with Venclexta.

Taking other medicines

Do not take Venclexta and talk to your doctor if you take a medicine that contains:

ketoconazole, posaconazole, voriconazole or itraconazole, medicines used for fungal infections
clarithromycin, a medicine used to treat bacterial infections
conivaptan, a medicine used to treat low sodium levels
ritonavir, indinavir, lopinavir or telaprevir, medicines used to treat HIV or HCV infections.

For patients with AML, your doctor may choose to reduce the starting dose of Venclexta or provide other advice on how your treatment should be managed.

Serious or life-threatening effects can occur when Venclexta is taken with certain medicines, when treatment starts and during the time when the dose is increased.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Your doctor may need to stop certain medicines when you first start taking Venclexta and when your dose is gradually increased to the full standard dose.

If your are taking certain medications that can interact with Venclexta, your doctor may also choose to reduce the starting dose.

Some medicines and Venclexta may interfere with each other.

Tell your doctor if you are taking:

fluconazole, a medicine used to treat fungal infections
ciprofloxacin, erythromycin, azithromycin, nafcillin or rifampicin, medicines called antibiotics that are used to treat bacterial infections
carbamazepine or phenytoin, medicines used to prevent seizures or to treat epilepsy
efavirenz or etravirine, medicines used to treat HIV infection
captopril, carvedilol, felodipine, ranolazine, bosentan, verapamil or diltiazem, medicines used to treat blood pressure or angina
modafinil, a medicine used to treat a sleep disorder known as narcolepsy
herbal medicines: St. John's Wort (Hypericum perforatum) or quercetin
warfarin, a medicine used to thin the blood
amiodarone, quinidine, ticagrelor, digoxin or dronedarone, medicines used to treat heart failure or heart rhythm problems
everolimus or sirolimus, medicines used to treat cancer and patients who have had organ transplants
ciclosporin, a medicine used to suppress the immune system.

These medicines may be affected by Venclexta, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Venclexta.

How to take Venclexta

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

It is important you follow the instructions your doctor provides about how to take Venclexta and for how long. Not taking the medicine as directed or stopping the medicine too early may cause you to not respond to the medicine, may affect your response to future treatments, and may increase the risk of side effects

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

Take Venclexta exactly as your doctor has prescribed. Your doctor will tell you how many tablets to take and at what time of the day.

CLL
For patients with CLL, you will begin treatment with Venclexta at a low dose for 1 week. Your doctor will gradually increase the dose over the next four weeks to the full standard dose.

Week 1: The starting dose is 20 mg (two 10 mg tablets) once a day
Week 2: The dose is 50 mg (one 50 mg tablet) once a day
Week 3: The dose is 100 mg (one 100 mg tablet) once a day
Week 4: The dose 200 mg (two 100 mg tablets) once a day
Week 5 and onwards: The dose is 400 mg (four 100 mg tablets) once a day. You will stay on the 400 mg daily dose, which is the standard dose, for as long as your doctor determines is necessary.

AML
For patients with AML taking Venclexta in combination with azacitidine:

You will begin treatment with Venclexta at a low dose. Your doctor will gradually increase the dose over the next three days to the full standard dose.

The starting dose is 100 mg (one 100 mg tablet) once a day for 1 day
Day 2: The dose will be increased to 200 mg (two 100 mg tablets) once a day for 1 day
Day 3 and onwards: The dose will be increased to 400 mg (four 100 mg tablets) once a day. You will stay on the 400 mg daily dose, which is the standard dose, for as long as your doctor determines it necessary.

For patients with AML taking Venclexta in combination with lowdose cytarabine:

You will begin treatment with Venclexta at a low dose. Your doctor will gradually increase the dose over the next four days to the full standard dose.

The starting dose is 100 mg (one 100 mg tablet) once a day for 1 day
Day 2: The dose will be increased to 200 mg (two 100 mg tablets) once a day for 1 day
Day 3: The dose will be increased to 400 mg (four 100 mg tablets) once a day for 1 day
Day 4 and onwards: The dose will be increased to 600 mg (six 100 mg tablets) once a day. You will stay on the 600 mg daily dose, which is the standard dose, for as long as your doctor determines it necessary.

Ask your doctor or pharmacist if you are unsure.

Your doctor may change the dose of Venclexta you take based on test results during treatment.

Follow all of the instructions of your doctor and pharmacist. If you are being treated for CLL, also refer to the Quick Start Guide provided with your monthly starting pack for instructions on which tablets to take and when to take them.

If you are not sure how much and when to take it, ask your doctor or pharmacist.

How to take it

Swallow the tablets whole with a glass of water.

Do not chew, crush, or break the tablets.

Do not drink grapefruit juice, eat grapefruit, starfruit or Seville oranges or marmalades while you are taking Venclexta. These products may increase the amount of Venclexta in your blood.

When to take it

Take Venclexta during or immediately after a meal, at about the same time every day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps control your condition, but it does not cure it. It is important to keep taking your medicine even if you feel well.

If you become pregnant while taking Venclexta, you should immediately stop taking it and tell your doctor.

If you vomit after taking it

Do not take any additional dose that day. Take the dose at the usual time the next day.

If you forget to take it

It is important not to miss a dose of this medicine.

If you do miss a dose of Venclexta:

By less than 8 hours
- Take the missed dose with food as soon as possible. Take your next dose the following day as usual.
By more than 8 hours
- Do not take the dose that day. Take your next dose at your usual time the next day.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your doctor or pharmacist for advice.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Venclexta. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Venclexta

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Venclexta.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon that you are taking this medicine.

Tell your doctor immediately if you become pregnant while taking Venclexta.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Tell your doctor if, for any reason, you have not used Venclexta as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily. You may also be at a greater risk of experiencing side effects if you do not take Venclexta as directed.

Things you must not do

Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop taking Venclexta, or change the dosage, without checking with your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Venclexta affects you. The effect of Venclexta on your ability to drive or use machines is not known.

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, symptoms such as nausea or vomiting may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Venclexta.

All medicines have some side effects. Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side-effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

feeling very tired
feeling sick
unusual weakness or lack of energy
tiredness, headaches, being short of breath when exercising, dizziness and looking pale. These are symptoms of anaemia
bruising or bleeding more than normal (e.g. blood in your urine or faeces, nose bleeds)
diarrhoea and vomiting
constipation
decreased appetite
dizziness
headache
cough
shortness of breath, difficulty breathing or chest tightness.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor or pharmacist as soon as possible if you notice any of the following:

fever
chills
feeling weak or confused
cough
pain or burning feeling when passing urine.

These are possible signs of infection. Your doctor may check your blood count during treatment with Venclexta. Low white blood cell count (known as neutropenia) can increase your risk of infection.

Some infections can be very serious.

Tell your doctor immediately if you have signs of an infection while taking Venclexta.

Tell your doctor or pharmacist immediately if you notice any of the following:

fever or chills
feeling or being sick (nausea or vomiting)
feeling confused
feeling short of breath
irregular heart beat
dark or cloudy urine
fits or seizures
feeling unusually tired
muscle pain or joint discomfort.

These symptoms can be associated with TLS. Refer to the section of this leaflet titled "Tumour Lysis Syndrome" for further information on TLS.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

After using Venclexta

Storage

Keep your tablets in the pack/bottle until it is time to take them.

Keep the medicine in a cool, dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill. Do not leave it in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or the medicine has passed its expiry date, return any of the unused medicine to your pharmacist for disposal.

Product description

What it looks like

Venclexta tablets come in three strengths:

Venclexta 10 mg film-coated tablets are pale yellow, round 6 mm diameter, with "V" on one side and "10" on the other,
Venclexta 50 mg film-coated tablets are beige, oblong 14 mm long, with "V" on one side and "50" on the other,
Venclexta 100 mg film-coated tablets are pale yellow, oblong 17 mm long, with "V" on one side and "100" on the other.

For patients with CLL, Venclexta is available as a Starting Pack, which is designed to provide you with the first four weeks of your dosing regimen.

Each starting pack is presented as a carton containing four weekly wallets:

Week 1 (14 x 10 mg tablets)
Week 2 (7 x 50 mg tablets)
Week 3 (7 x 100 mg tablets)
Week 4 (14 x 100 mg tablets)

The 100 mg strength is also available as a bottle (containing 120 or 180 tablets) and a blister pack (containing 7, 14 or 112 tablets).

Not all presentations may be available.

Ingredients

Active Ingredient
The active ingredient is venetoclax. Each film-coated tablet contains 10 mg, 50 mg or 100 mg venetoclax.

Inactive ingredients

copovidone
colloidal anhydrous silica
polysorbate 80
sodium stearylfumarate
calcium hydrogen phosphate
iron oxide yellow
iron oxide red (50 mg tablet only)
iron oxide black (50 mg tablet only)
polyvinyl alcohol
macrogol 3350
purified talc
titanium dioxide

Venclexta does not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Venclexta is supplied in Australia by:

AbbVie Pty Ltd
241 O'Riordan Street
Mascot NSW 2020
Australia

This leaflet was prepared in February 2020.

Australian Registration Number(s)
AUST R 267441, 267442, 267443, 267444, 267445.

Version 6

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Venclexta

Active ingredient

Venetoclax

Schedule

1 Name of Medicine

Venetoclax.

2 Qualitative and Quantitative Composition

Venclexta 10 mg tablets.

Each film-coated tablet contains 10 mg venetoclax.

Venclexta 50 mg tablets.

Each film-coated tablet contains 50 mg venetoclax.

Venclexta 100 mg tablets.

Each film-coated tablet contains 100 mg venetoclax.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Film-coated tablet.

Venclexta 10 mg tablets.

Round, biconvex shaped, pale yellow debossed with "V" on one side and "10" on the other side.

Venclexta 50 mg tablets.

Oblong, biconvex shaped, beige debossed with "V" on one side and "50" on the other side.

Venclexta 100 mg tablets.

Oblong, biconvex shaped, pale yellow debossed with "V" on one side and "100" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Venclexta in combination with obinutuzumab is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL).
Venclexta in combination with ibrutinib is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).
Venclexta in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.
Venclexta monotherapy is indicated for the treatment of:
patients with relapsed or refractory CLL with 17p deletion, or;
patients with relapsed or refractory CLL for whom there are no other suitable treatment options.

Acute myeloid leukaemia.

Venclexta, in combination with azacitidine or low-dose cytarabine, is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

4.2 Dose and Method of Administration

Patients should be instructed to take Venclexta tablets with a meal and water at approximately the same time each day. Venclexta tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

5-week ramp-up schedule. The starting dose of Venclexta is 20 mg once daily for 7 days. The Venclexta dose must be administered according to a weekly ramp-up schedule to the daily dose of 400 mg over a period of 5 weeks as shown in Table 1. The 5 week ramp-up schedule is designed to gradually reduce tumour burden (debulking) and decrease the risk of tumour lysis syndrome (TLS).

First line CLL/SLL.

Venclexta in combination with obinutuzumab.

Venclexta should be given for a total of 12 cycles (28 days in each cycle): 6 cycles in combination with obinutuzumab, followed by 6 cycles of Venclexta as a single agent as shown in Table 2. Refer to the obinutuzumab Product Information for prophylaxis of tumour lysis syndrome and infusion related reactions.

Venclexta in combination with ibrutinib.

Start ibrutinib (420 mg once daily) as a single agent for 3 cycles (28 days in each cycle), followed by 12 cycles of Venclexta in combination with ibrutinib. Beginning on Cycle 4 Day 1, administer Venclexta according to the ramp-up schedule (see Table 1). After completing the ramp-up schedule, patients should continue Venclexta 400 mg once daily in combination with ibrutinib 420 mg orally once daily to the end of Cycle 15.
Refer to the ibrutinib Product Information for additional information.
Previously treated CLL/SLL.

Venclexta in combination with rituximab.

Start rituximab administration after the patient has completed the ramp-up schedule with Venclexta (see Table 1) and has received a daily 400 mg dose of Venclexta for 7 days.
Patients should continue Venclexta 400 mg once daily for up to 24 months from cycle 1 day 1 of rituximab in the absence of disease progression or unacceptable toxicity.

Venclexta as monotherapy.

The recommended dose of Venclexta is 400 mg once daily after the patient has completed the ramp-up schedule.
Treatment should continue until disease progression or Venclexta is no longer tolerated by the patient.

Acute myeloid leukaemia.

The dose of Venclexta depends upon the combination agent. The Venclexta dosing schedule (including ramp-up) is shown in Table 3.

Initiate azacitidine or low-dose cytarabine on cycle 1 day 1.
Azacitidine should be administered at 75 mg/m² either intravenously or subcutaneously on days 1-7 of each 28-day cycle beginning on cycle 1 day 1.
Cytarabine should be administered at a dose of 20 mg/m² subcutaneously once daily on days 1-10 of each 28-day cycle beginning on cycle 1 day 1.
Interrupt Venclexta dosing as needed for management of haematological toxicities and blood count recovery (see Section 4.2 Dose and Method of Administration, Dose modifications based on adverse reactions). Refer to the azacitidine or cytarabine Product Information for additional information.
Venclexta, in combination with azacitidine or low-dose cytarabine, should be continued until disease progression or unacceptable toxicity is observed.

Risk assessment and prophylaxis for TLS.

Patients treated with Venclexta may develop TLS. Refer to the appropriate section below for specific details on management. Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and anti-hyperuricaemics to patients prior to first dose of Venclexta to reduce risk of TLS.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Venclexta can cause rapid tumour reduction and thus poses a risk for TLS in the initial 5 week ramp-up phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclexta and at each dose increase.
The risk of TLS is a continuum based on multiple factors, including comorbidities, particularly reduced renal function (creatinine clearance [CrCl] < 80 mL/min), and tumour burden. Splenomegaly may contribute to the overall TLS risk. The risk may decrease as tumour burden decreases with Venclexta treatment (see Section 4.4 Special Warnings and Precautions for Use). Perform tumour burden assessments, including radiographic evaluation (e.g. CT scan). Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with Venclexta.

Prophylaxis for tumour lysis syndrome.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Table 4 describes the recommended TLS prophylaxis and monitoring during Venclexta treatment based on tumour burden determination from clinical trial data. In addition, consider all patient comorbidities for risk-appropriate prophylaxis and monitoring, either outpatient or in hospital.

Acute myeloid leukaemia.

The Venclexta daily dose ramp-up is 3 days with azacitidine, or 4 days with low-dose cytarabine (see Table 3).
Follow these TLS prophylaxis measures:
All patients should have white blood cell count < 25 x 10⁹/L prior to initiation of Venclexta and cytoreduction prior to treatment may be required.
All patients should be adequately hydrated and receive anti-hyperuricaemic agents prior to initiation of the first dose of Venclexta and during the ramp-up phase.
Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with Venclexta.
Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up and 24 hours after reaching the final dose.
For patients with risk factors for TLS (e.g. circulating blasts, high burden of leukaemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reduced Venclexta starting dose.

Dose modifications based on adverse reactions.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Dosing interruption and/or dose reduction for adverse reactions may be required. See Table 5 and Table 6 for recommended dose modifications for haematological and other adverse reactions related to Venclexta.
For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks after completing the ramp up phase, reassess the risk of TLS to determine if re-initiation with a reduced dose is necessary (e.g. at one of the prior levels of the ramp up schedule) (see Section 4.2 Dose and Method of Administration, Chronic lymphocytic leukaemia/small lymphocytic lymphoma, 5-week ramp-up schedule, Risk assessment and prophylaxis for tumour lysis syndrome (TLS), and Prophylaxis for tumour lysis syndrome).

Acute myeloid leukaemia.

Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. Dose modifications of Venclexta for adverse reactions are provided in Table 7.

Dose modifications for use with CYP3A inhibitors.

Concomitant use of Venclexta with strong or moderate CYP3A inhibitors increases venetoclax exposure (i.e. C_max and AUC) and may increase the risk for TLS at initiation and during dose ramp-up.
In patients with CLL/SLL, concomitant use of Venclexta with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated (see Section 4.3 Contraindications).
In all patients, if a CYP3A inhibitor is to be used concomitantly, follow the recommendations for Venclexta dose modifications summarised in Table 8. Monitor these patients more closely for signs of toxicities (see Section 4.2 Dose and Method of Administration, Dose modifications based on adverse reactions).
The Venclexta dose that was used prior to initiating a CYP3A inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor (see Section 4.2 Dose and Method of Administration, Dose modifications based on adverse reactions; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Missed dose.

If the patient misses a dose of Venclexta within 8 hours of the time it is usually taken, the patient should be instructed to take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose but resume the usual dosing schedule the next day.
If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.

4.3 Contraindications

Hypersensitivity to venetoclax, or to any of the excipients within the formulation.
In patients with CLL or SLL, concomitant use of Venclexta with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Tumour lysis syndrome.

Tumour lysis syndrome (TLS), including life threatening or fatal events and renal failure requiring dialysis, has occurred in patients treated with Venclexta (see Section 4.8 Adverse Effects (Undesirable Effects)).
Interrupt or discontinue Venclexta, as recommended, if this adverse event occurs. When restarting Venclexta, follow the dose modifications guidance (see Section 4.2 Dose and Method of Administration).
Venclexta can cause rapid tumour reduction and thus poses a risk for TLS at initiation and during the ramp-up phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6-8 hours following the first dose of Venclexta and at each dose increase.
The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden (see Table 4) and splenomegaly in CLL (see Section 4.2 Dose and Method of Administration).
All patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. Blood chemistries should be monitored and abnormalities managed promptly. Employ more intensive measures (intravenous hydration, frequent monitoring, and hospitalisation) as overall risk increases (see Section 4.2 Dose and Method of Administration).
Concomitant use of Venclexta with strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk of TLS at initiation and during ramp-up phase (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Inhibitors of P-gp may also increase venetoclax exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Neutropenia.

In patients with CLL/SLL, grade 3 or 4 neutropenia developed in 63% to 64% of patients and grade 4 neutropenia developed in 31% to 33% of patients treated with Venclexta in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients treated with Venclexta in combination and monotherapy studies (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients with AML, grade 3 or 4 neutropenia is common before starting treatment. The neutrophil counts can worsen with Venclexta in combination with azacitidine or low-dose cytarabine. Neutropenia can recur with subsequent cycles of therapy. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or dose reductions are recommended for severe neutropenia. Supportive measures should be considered, including antimicrobials for any signs of infection, and use of growth factors (e.g. granulocyte colony stimulating factor [G-CSF]) (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties for further information on potential interactions with CYP3A inhibitors/inducers).

Serious infection.

Serious infections, including events of sepsis and events with fatal outcome, have been reported in patients treated with Venclexta (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients for fever and any symptoms of infection and treat promptly. Interrupt dosing as appropriate.

Immunisation.

The safety and efficacy of immunisation with live attenuated vaccines during or following Venclexta therapy have not been studied. Do not administer live attenuated vaccines prior to, during, or after treatment with Venclexta until B-cell recovery occurs.

Hepatic impairment.

No dose adjustment is recommended in patients with mild or moderate hepatic impairment based on results of the population pharmacokinetic analysis.
A 50% dose reduction throughout treatment is recommended for patients with severe hepatic impairment; monitor these patients more closely for signs of toxicity (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No specific clinical trials have been conducted in subjects with renal impairment. After a single oral administration of 200 mg radiolabeled [¹⁴C]-venetoclax to healthy subjects, less than 0.1% of radioactive Venclexta dose was detected in urine. No dose adjustment is needed for patients with mild, moderate or severe renal impairment (CrCl ≥ 15 mL/min) based on the results of the population pharmacokinetic analysis (see Section 5.2 Pharmacokinetic Properties).
Patients with reduced renal function (CrCl < 80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with Venclexta (see Section 4.2 Dose and Method of Administration). A recommended dose has not been determined for patients with (CrCl < 15 mL/min) or patients on dialysis.

Paediatric use.

The safety and efficacy of Venclexta in children and adolescents younger than 18 years have not been established.

Use in the elderly.

No specific dose adjustment is required for elderly patients (aged ≥ 65 years).
Of the 194 patients with previously treated CLL who received venetoclax in combination with rituximab 50% were 65 years or older.
Of the 164 previously treated patients with CLL or SLL evaluated for efficacy by an Independent Review Committee in Studies M13-982 and M12-175, 91 (55.5%) patients were ≥ 65 years of age and 28 (17.1%) patients were ≥ 75 years of age.
Of the 240 patients with CLL evaluated for safety from 3 open-label clinical trials, 138 (57.5%) patients were ≥ 65 years of age and 40 (16.7%) patients were ≥ 75 years of age.
There were no overall differences in safety or efficacy observed between older and younger patients in combination and monotherapy studies.

Increased mortality in patients with multiple myeloma (not an approved indication) when Venclexta is added to bortezomib and dexamethasone.

In a randomised trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of Venclexta to bortezomib plus dexamethasone, a use for which Venclexta is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with Venclexta in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential effects of other medicines on Venclexta.

Venetoclax is predominantly metabolised by CYP3A4.

CYP3A inhibitors.

Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days in 11 previously treated patients with NHL increased venetoclax C_max by 130% and AUC_∞ by 540%.
Co-administration of 50 mg once daily ritonavir, a strong CYP3A, P-gp and OATP1B1/B3 inhibitor, for 14 days in 6 healthy subjects increased venetoclax C_max by 140% and AUC by 690%.
Findings from a drug interaction sub-study (M14-358) involving 12 newly diagnosed patients with AML determined that, when compared to steady state conditions amongst the same patients receiving venetoclax 400 mg a day, the co-administration of 300 mg posaconazole (a strong CYP3A and P-gp inhibitor) with venetoclax 50 mg and 100 mg resulted in 61% and 86% higher venetoclax C_max levels and 90% and 144% higher AUC₂₄ respectively.
For patients requiring concomitant use of Venclexta with strong CYP3A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, conivaptan, indinavir, lopinavir, telaprevir, and ritonavir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, diltiazem, erythromycin, dronedarone, fluconazole, verapamil) administer Venclexta dose according to Table 8. Monitor patients more closely for signs of Venclexta toxicities (see Section 4.2 Dose and Method of Administration).
The Venclexta dose that was used prior to initiating the CYP3A inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor (see Section 4.2 Dose and Method of Administration).
Avoid grapefruit products, Seville oranges, and starfruit during treatment with Venclexta, as they contain inhibitors of CYP3A.

OATP1B1/1B3 and P-gp inhibitors.

Co-administration of a 600 mg single dose of rifampicin, an OATP1B1/1B3 and P-gp inhibitor, in 11 healthy subjects increased venetoclax C_max by 106% and AUC_∞ by 78%.
Concomitant use of venetoclax with P-gp inhibitors (e.g. amiodarone, captopril, carvedilol, ciclosporin, felodipine, quercetin, quinidine, ranolazine, ticagrelor) at initiation and during the ramp-up phase should be avoided; if a P-gp inhibitor must be used, patients should be monitored closely for signs of toxicities.

Azithromycin.

Co-administration of 500 mg of azithromycin on the first day followed by 250 mg of azithromycin for 4 days in 12 healthy subjects decreased venetoclax C_max by 25% and AUC_∞ by 35%. No dose adjustment is needed when venetoclax is co-administered with azithromycin.

CYP3A inducers.

Co-administration of 600 mg once daily rifampicin, a strong CYP3A inducer, for 13 days in 10 healthy subjects decreased venetoclax C_max by 42% and AUC_∞ by 71%. Concomitant use of Venclexta with strong CYP3A inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John's wort (Hypericum perforatum)) or moderate CYP3A inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. Alternative treatments with less CYP3A induction should be considered (see Section 5.2 Pharmacokinetic Properties).

Gastric acid-reducing agents.

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

Potential effects of Venclexta on other medicines.

Warfarin.

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

P-gp substrates.

Administration of a single 100 mg dose of venetoclax with 0.5 mg digoxin, a P-gp substrate, in 10 healthy subjects resulted in a 35% increase in digoxin C_max and a 9% increase in digoxin AUC_∞. Therefore, co-administration of narrow therapeutic index P-gp substrates (e.g. digoxin, everolimus, and sirolimus) with Venclexta should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before Venclexta.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of venetoclax on fertility are available. Based on findings in animals, male fertility may be compromised by treatment with Venclexta.
Fertility and early embryonic development studies with venetoclax were conducted in male and female mice. These studies evaluated mating, fertilisation, and embryonic development through implantation. There were no effects of venetoclax on oestrus cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day (in male and female mice, approximately 1.8 times the human AUC exposure at the maximum recommended clinical dose of 600 mg/day). However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at all dose levels examined (exposures of 0.3 to 11 times the human AUC exposure at the 600 mg/day clinical dose). Reversibility of this finding has not been demonstrated.
(Category C)
There are no adequate and well controlled studies of venetoclax in pregnant women. Based on embryofetal toxicity observed in mice, Venclexta may have effects on the fetus when administered to pregnant women.
Venclexta should not be used during pregnancy. Women of childbearing potential must use highly effective contraceptive measures during treatment with Venclexta and for at least 30 days after the last dose of treatment. If venetoclax is used during pregnancy or if the patient becomes pregnant while taking Venclexta, the patient should be apprised of the potential hazard to a fetus. The time period following treatment with Venclexta where it is safe to become pregnant is unknown.
Women of childbearing potential should undergo pregnancy testing before initiation of Venclexta.
In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits. These studies evaluated potential effects after implantation and subsequent embryo-fetal development during the respective periods of major organogenesis in mice and rabbits. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal bodyweight at 150 mg/kg/day (maternal exposures approximately 0.7 times the human AUC exposure at the maximum recommended clinical dose of 600 mg/day). In rabbits, venetoclax at 300 mg/kg/day produced maternal toxicity, but no fetal toxicity (maternal exposures approximately 0.09 times the human AUC exposure at the 600 mg/day clinical dose). No teratogenicity was observed in either the mouse or the rabbit. Additionally, administration of M27, the major human metabolite of venetoclax, at oral doses up to 250 mg/kg/day did not produce embryo-fetal toxicity or teratogenicity in a study in mice. Maternal exposure to M27 at this dose was approximately 9 times the human M27 AUC exposure at a dose of 400 mg/day of venetoclax. Limited placental transfer of venetoclax was shown in mice, rats and rabbits. Significant placental transfer of the M27 metabolite was evident in mice.
It is not known whether venetoclax or its metabolites are excreted in human breast milk. Venetoclax was shown to be readily excreted in milk in rats, along with trace amounts of metabolites. A risk to newborns/infants cannot be excluded. Because many drugs are excreted in human breast milk and because the potential for serious adverse reactions in breastfed infants from Venclexta is unknown, nursing women should be advised to discontinue breastfeeding during treatment with Venclexta.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Venclexta on the ability to drive and use machines have been performed. The pharmacological activity and adverse events reported to date do not indicate that such an effect is likely.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

Tabulated list of adverse events and reactions.

Adverse events and reactions are listed below by MedDRA body system organ class, rate and frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing rate.

Clinical trial experience in CLL/SLL.

Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.
Venclexta in combination with obinutuzumab. The safety of venetoclax in combination with obinutuzumab versus obinutuzumab and chlorambucil was evaluated in an open-label randomised (1:1) phase 3 study (CLL14) in patients with previously untreated CLL and coexisting medical conditions. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials, Venclexta in combination with obinutuzumab.
At the time of data analysis, the median duration of exposure to venetoclax was 10.5 months (range: 1 to 13.5 months). The median number of cycles was 6 for obinutuzumab and 12 for chlorambucil.
In the venetoclax + obinutuzumab arm, adverse events led to discontinuation in 16% of patients, dose reductions in 21% of patients and dose interruptions in 74% of patients. The most common adverse reaction that led to dose interruption of venetoclax was neutropenia.
In the venetoclax + obinutuzumab arm, fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection. Serious adverse reactions were reported in 49% of patients in the venetoclax + obinutuzumab arm, most often due to febrile neutropenia and pneumonia (5% each).
Table 9 provides the adverse events reported in CLL14.

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

Blood and lymphatic system disorders.

Febrile neutropenia (6%), lymphopenia (1%).

Infection and infestation disorder.

Pneumonia (8%), upper respiratory tract infection (8%), urinary tract infection (5%), sepsis^a (4%).

Investigations.

Blood creatinine increased (3%).

Metabolism and nutrition disorder.

Hyperuricaemia (4%), hyperkalaemia (2%), hyperphosphataemia (2%), hypocalcaemia (1%), tumour lysis syndrome (1%).
^a Includes the following terms: sepsis, septic shock and urosepsis.
Published data. In the CLL13 study identified in the literature (Eichhorst et al. 2023), the safety of venetoclax in combination with obinutuzumab versus chemo-immunotherapy (fludarabine, cyclophosphamide, rituximab [FCR] or bendamustine and rituximab [BR]) was evaluated in a phase 3 open-label randomised study in fit patients with previously untreated CLL without 17p deletion or TP53 mutation. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials, Venclexta in combination with obinutuzumab. Table 10 provides the adverse events reported in CLL13.

Venclexta in combination with ibrutinib.

GLOW (CLL3011).

GLOW was an open-label randomised (1:1) phase 3 study in patients with previously untreated CLL/SLL who were 65 years or older, or patients < 65 years of age with a Cumulative Illness Rating Scale (CIRS) score > 6 or CrCL < 70 mL/min. Patients received 3 cycles of single-agent ibrutinib (420 mg/day orally). Starting at Cycle 4, venetoclax was added (starting with the 5-week dose ramp-up to the recommended daily dose of 400 mg) to the ibrutinib regimen continuously for 12 additional cycles.
At the time of primary data analysis (26 February 2021), the median duration of exposure was 13.8 months in the Venclexta + ibrutinib arm and 5.13 months in the chlorambucil + obinutuzumab arm.
In the Venclexta + ibrutinib arm, adverse events led to discontinuation of Venclexta in 11% of patients, dose reductions in 17% of patients, and dose interruptions in 42% of patients. The most common adverse reaction that led to dose interruption of Venclexta was neutropenia.
Table 11 provides the adverse events reported in GLOW.

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

Blood and lymphatic system disorders.

Febrile neutropenia (2%), lymphocyte count decreased (< 1%).

Infections and infestations.

Sepsis^a (< 1%).

Investigations.

Blood creatinine increased (5%).

Metabolism and nutrition disorders.

Hyperkalemia^b (9%), hyperuricemia^c (7%), hypocalcemia^d (4%).
^a Includes septic shock. ^b Includes hyperkalemia and blood potassium increased. ^c Includes hyperuricemia and blood uric acid increased. ^d Includes hypocalcemia and blood calcium decreased.

CAPTIVATE (PCYC-1142-CA).

The safety of Venclexta in combination with ibrutinib was evaluated in a multi-center, 2 cohort study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration (FD) therapy in adult patients who were 70 years or younger with previously untreated CLL or SLL. Patients in both cohorts received 3 cycles of single-agent ibrutinib (420 mg/day orally). Starting at Cycle 4, venetoclax was added (starting with the 5-week dose ramp-up to the recommended daily dose of 400 mg) to the ibrutinib regimen continuously for at least 12 additional cycles. Safety was assessed in an all-treated pool consisting of the MRD-guided cohort (first 16 cycles) plus the FD cohort.
At the time of primary data analysis (12 November 2020), the median duration of exposure was 11.5 months for venetoclax and 14.1 months for ibrutinib.
Adverse events led to discontinuation of Venclexta in 3% of patients and dose reductions in 12% of patients.
Table 12 provides the adverse events reported in CAPTIVATE.

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

Blood and lymphatic system disorders.

Anaemia (7%), febrile neutropenia (1%), lymphopenia^a (< 1%).

Infections and infestations.

Urinary tract infection (7%), pneumonia^b (4%), sepsis^c (1%).

Investigations.

Blood creatinine increased (6%).

Metabolism and nutrition disorders.

Hyperphosphatemia^d (7%), hyperuricemia^e (7%), hyperkalemia^f (6%), hypocalcemia^g (3%), tumour lysis syndrome (< 1%; 1 patient in MRD [first 16 cycles] cohort).
^a Includes lymphopenia and lymphocyte count decreased. ^b Includes pneumonia, pleurisy viral, pneumonia bacterial. ^c Includes bacteraemia, disseminated varicella zoster virus infection, Escherichia bacteremia, staphylococcal bacteraemia. ^d Includes hyperphosphatemia and blood phosphorus increased. ^e Includes hyperuricemia and blood uric acid increased. ^f Includes hyperkalemia and blood potassium increased. ^g Includes hypocalcemia and blood calcium decreased.
Venclexta in combination with rituximab. The safety of venetoclax in combination with rituximab versus bendamustine in combination with rituximab, was evaluated in an open-label randomised phase 3 study (MURANO), in patients with CLL who have received at least one prior therapy. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials, Venclexta in combination with rituximab. At the time of data analysis, the median duration of exposure was 22 months in the venetoclax + rituximab arm compared to 6 months in the bendamustine plus rituximab arm.
Discontinuations due to adverse events occurred in 16% of patients treated with venetoclax + rituximab. Dose reductions due to adverse events occurred in 15% of patients treated with venetoclax + rituximab. Dose interruptions due to adverse events occurred in 71% of patients treated with venetoclax + rituximab. The most common adverse reaction that led to dose interruption of venetoclax was neutropenia. See Table 13.

Based on the existing safety profile of Venclexta, adverse reactions reported in the venetoclax + rituximab arm of MURANO that fall below the cut-off in Table 13 are presented below by MedDRA body system organ class and by frequency.

Blood and lymphatic system disorders.

Anaemia (very common), febrile neutropenia (common), lymphopenia/lymphocyte count decreased (common).

Gastrointestinal disorders.

Nausea (very common), constipation (very common), vomiting (common).

General disorders and administration site conditions.

Fatigue (very common).

Infections and infestations.

Pneumonia (common), sepsis (common).

Investigations.

Blood creatinine increased (common).

Metabolism and nutrition disorders.

Tumour lysis syndrome (common), hyperuricaemia (common), hypocalcaemia (common).
During treatment with single agent Venclexta after completion of venetoclax + rituximab combination treatment, the most common all grade adverse events (≥ 5% patients) reported were diarrhoea (19%), neutropenia (14%), upper respiratory tract infection (12%), bronchitis (6%), cough (6%), fatigue (6%), nausea (6%), nasopharyngitis (5%), pyrexia (5%), rash (5%), and sinusitis (5%); the most common grade ≥ 3 adverse events (≥ 2% patients) were neutropenia (11%), anaemia (3%), pneumonia (2%), and thrombocytopenia (2%).
Venclexta as monotherapy. The safety of Venclexta is based on pooled data of 352 patients with R/R CLL/SLL treated with Venclexta (400 mg once daily cohort who received at least one dose) in two phase 2 trials (Study M13-982 enrolled patients with previously treated CLL with 17p deletion and Study M14-032 enrolled patients with CLL who had failed an inhibitor of the B-cell receptor pathway), and one phase 1 trial (Study M12-175 enrolled patients with previously treated CLL or SLL, including those with 17p deletion). In the overall safety population, there were 212 patients with 17p deletion and 148 patients who had failed an inhibitor of the B cell receptor pathway. Patients were treated with Venclexta 400 mg monotherapy once daily following the ramp-up schedule.
The frequencies of adverse drug reactions (ADRs) reported with Venclexta are summarised in Table 14.

The most frequently reported serious adverse reactions (≥ 2%) unrelated to disease progression were pneumonia and febrile neutropenia.
Discontinuations due to adverse events occurred in 10.5% of patients.
Dosage reductions due to adverse events occurred in 14% of patients. Dose interruptions due to adverse events occurred in 40% of patients. Of the most frequent adverse events (≥ 4%) leading to dose reductions or interruptions, the one identified as adverse reaction was neutropenia (5% and 4%, respectively).

Clinical trial experience in AML.

Venclexta in combination with azacitidine.

VIALE-A.

The safety of Venclexta in combination with azacitidine (N = 283) versus placebo with azacitidine (N = 144) was evaluated in a double-blind randomised phase 3 study in patients with newly diagnosed AML. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials, Venclexta in combination with azacitidine.
The median duration of treatment was 7.6 months (range: < 0.1 to 30.7 months) in the Venclexta in combination with azacitidine arm and 4.3 months (range: 0.1 to 24.0 months) in the placebo with azacitidine arm. The median number of cycles of azacitidine was 7 (range: 1 to 30) in the Venclexta in combination with azacitidine arm and 4.5 (range: 1 to 26) in the placebo with azacitidine arm.
In the Venclexta in combination with azacitidine arm, adverse reactions led to permanent venetoclax treatment discontinuations in 24% of patients, venetoclax dose reductions in 2%, and venetoclax dose interruptions in 72%. In the Venclexta in combination with azacitidine arm, no event led to venetoclax discontinuation in ≥ 5% of patients. In the placebo with azacitidine arm, adverse reactions led to placebo treatment discontinuations in 20% of patients, placebo dose reductions in 4%, and placebo dose interruptions in 57%.
The most frequent adverse reactions (≥ 5%) leading to venetoclax dose interruptions in the Venclexta in combination with azacitidine arm were febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), thrombocytopenia (10%), and sepsis (8%). In the placebo with azacitidine arm, the most frequent adverse reaction (≥ 5%) leading to placebo dose interruption were pneumonia (14%), neutropenia (10%), and sepsis (6%). Among patients who achieved bone marrow clearance of leukaemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) < 500/microlitre.
In the Venclexta in combination with azacitidine arm, fatal adverse reactions occurred in 23% of patients, with the most frequent (≥ 2%) being pneumonia (4%) and sepsis (4%). In the placebo with azacitidine arm, fatal adverse reactions were reported in 20% of patients.
In the Venclexta in combination with azacitidine arm, serious adverse reactions were reported in 83% of patients, with most frequent (≥ 5%) being febrile neutropenia (30%), pneumonia (23%), and sepsis (16%). In the placebo with azacitidine arm, serious adverse reactions were reported in 73% of patients.
The 30-day and 60-day mortality rates observed with Venclexta in combination with azacitidine were 7% (21/283) and 15% (43/283), respectively.
Table 15 provides the adverse reactions reported in VIALE-A.

Other adverse reactions (all grades) reported in the venetoclax + azacitidine arm are presented below:

Gastrointestinal disorders.

Abdominal pain (11%).

Hepatobiliary disorders.

Cholecystitis/cholelithiasis^a (4%).

Infections and infestations.

Pneumonia^b (34%), urinary tract infection (9%).

Investigations.

Blood bilirubin increased (7%), weight decreased (13%).

Metabolism and nutrition disorders.

Hypokalaemia (29%), tumour lysis syndrome (1%).

Nervous system disorders.

Headache (11%).
^a Includes following terms: cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic.
^b Includes following terms: pneumonia, lung infection, bronchopulmonary aspergillosis, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, pneumonia viral, infectious pleural effusion, pneumonia haemophilus, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pulmonary mycosis, pulmonary nocardiosis, and tuberculosis.

Study M14-358.

The safety of Venclexta in combination with azacitidine (N = 84) was evaluated in a non-randomised study in patients with newly diagnosed AML.
Discontinuations of Venclexta due to adverse events occurred in 25% of patients. The most frequent adverse reactions leading to drug discontinuation (≥ 2%) were febrile neutropenia and pneumonia. Dosage interruptions of Venclexta due to adverse events occurred in 68% of patients. The most frequent adverse reactions leading to dose interruption (≥ 5%) were febrile neutropenia, neutropenia/neutrophil count decreased and pneumonia. Dosage reductions of Venclexta due to adverse reactions occurred in 1% of patients.
The most common adverse reactions (≥ 30%) of any grade were nausea (64%), diarrhoea (61%), thrombocytopenia/platelet count decreased (54%), neutropenia/neutrophil count decreased (46%), hypokalaemia (35%), febrile neutropenia (39%), vomiting (38%), fatigue (36%) and pneumonia^a (38%).
Serious adverse events were reported in 77% of patients. The most frequent serious adverse reactions (≥ 5%) were febrile neutropenia and pneumonia.
The 30-day and 60-day mortality rates observed with Venclexta in combination with azacitidine were 2.4% (2/84) and 8.3% (7/84), respectively.
^a Includes the following terms: pneumonia, lung consolidation, and pneumonia fungal.
Venclexta in combination with low-dose cytarabine.

VIALE-C.

The safety of Venclexta (600 mg daily dose) in combination with low-dose cytarabine (N = 142) versus placebo with low-dose cytarabine (N = 68) was evaluated in a double-blind randomised phase 3 study in patients with newly diagnosed AML (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Venclexta in combination with low-dose cytarabine).
The median duration of treatment was 4.1 months (range: < 0.1 to 23.5 months) in the Venclexta in combination with low-dose cytarabine arm and 1.7 months (range: 0.1 to 20.2 months) in the placebo with low-dose cytarabine arm. The median number of cycles of low-dose cytarabine was 4 (range: 1 to 22) in the Venclexta in combination with low-dose cytarabine arm and 2 (range: 1 to 22) (28 days per cycle) in the placebo with low-dose cytarabine arm.
In the Venclexta in combination with low-dose cytarabine arm, adverse reactions led to treatment discontinuations in 26% of patients, venetoclax dose reductions in 10%, and venetoclax dose interruptions in 63%. In the placebo with low-dose cytarabine arm, adverse reactions led to placebo treatment discontinuations in 24% of patients, placebo dose reductions in 7%, and placebo dose interruptions in 51%.
The most frequent adverse reaction leading to venetoclax discontinuation in the Venclexta in combination with low-dose cytarabine arm was pneumonia (7%); sepsis (4%) was the most frequent adverse reaction leading to discontinuation in the placebo with low-dose cytarabine arm.
The most frequent adverse reactions (≥ 2%) leading to dose reductions in the Venclexta in combination with low-dose cytarabine arm was thrombocytopenia (2%). The most frequent adverse reactions (≥ 5%) leading to dose interruption in the Venclexta in combination with low-dose cytarabine arm were neutropenia (23%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (8%), and anaemia (6%), and in the placebo with low-dose cytarabine arm were pneumonia (12%), thrombocytopenia (9%), febrile neutropenia (7%), neutropenia (6%), and sepsis (6%).
Among patients who achieved bone marrow clearance of leukaemia, 37% underwent dose interruptions for ANC < 500/microlitre.
Fatal adverse reactions were reported in 23% of patients in the Venclexta in combination with low-dose cytarabine arm, with the most frequent (≥ 5%) being pneumonia (5%). In the placebo with low-dose cytarabine arm, fatal adverse reactions were reported in 21% of patients.
Serious adverse reactions were reported in 67% of patients in the Venclexta in combination with low-dose cytarabine arm, with the most frequent (≥ 10%) being pneumonia (20%), febrile neutropenia (17%), and sepsis (13%). In the placebo with low-dose cytarabine arm, serious adverse reactions were reported in 62% of patients. The most frequent were febrile neutropenia (18%), sepsis (18%), and pneumonia (16%).
The 30-day and 60-day mortality rates observed with Venclexta in combination with low-dose cytarabine were 13% (18/142) and 20% (29/142), respectively.
Table 16 presents adverse reactions identified in the VIALE-C trial.

Other adverse drug reactions reported in the venetoclax + low-dose cytarabine arm are presented below:

Gastrointestinal disorder.

Stomatitis (10%).

General disorders and administration site conditions.

Fatigue (16%), asthenia (12%).

Hepatobiliary disorders.

Cholecystitis/cholelithiasis^a (2%).

Infections and infestations.

Sepsis^b (15%), urinary tract infection (7%).

Investigations.

Weight decreased (10%).

Metabolism and nutrition disorders.

Decreased appetite (22%), tumour lysis syndrome (6%).

Musculoskeletal and connective tissue disorders.

Arthralgia (8%).

Respiratory, thoracic, and mediastinal disorders.

Dyspnoea (8%).

Vascular disorders.

Hypotension (10%).
^a Includes following terms: cholecystitis acute, cholecystitis, and cholecystitis chronic.
^b Includes following terms: sepsis, septic shock, bacteraemia, neutropenic sepsis, bacterial sepsis, and staphylococcal sepsis.

Study M14-387.

The safety of Venclexta in combination with low-dose cytarabine (N = 82) was evaluated in a non-randomised study, in patients with newly diagnosed AML.
Discontinuations of Venclexta due to adverse events occurred in 33% of patients. The most frequent adverse reactions leading to venetoclax discontinuation (≥ 2%) were thrombocytopenia, sepsis and haemorrhage intracranial. Dosage interruptions of Venclexta due to adverse events occurred in 59% of patients. The most frequent adverse reactions leading to venetoclax interruption (≥ 5%) were thrombocytopenia and neutropenia. Dosage reductions of Venclexta due to adverse events occurred in 7% of patients. The most frequent adverse reaction leading to dose reduction (≥ 2%) was thrombocytopenia.
The most common adverse reactions (≥ 30%) of any grade were nausea (70%), thrombocytopenia/platelet count decreased (61%), diarrhoea (50%), hypokalaemia (49%), neutropenia/neutrophil count decreased (46%), febrile neutropenia (44%), fatigue (43%), decreased appetite (37%), anaemia/haemoglobin decreased (32%), and vomiting (30%).
Serious adverse events were reported in 91% of patients. The most frequent serious adverse reactions (≥ 5%) were febrile neutropenia, pneumonia and sepsis.

Tumour lysis syndrome.

Tumour lysis syndrome is an important identified risk when initiating Venclexta. TLS prophylaxis and monitoring measures are described in the Dosage and Administration section (see Section 4.2 Dose and Method of Administration).
Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Venclexta as monotherapy.

In the initial Phase 1 dose-finding trials, which had a relatively short (2-3 week) ramp-up phase and relatively high starting dose, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis.
The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures (see Section 4.2 Dose and Method of Administration). In venetoclax clinical trials, patients with any measurable lymph node ≥ 10 cm or those with both an ALC ≥ 25 x 10⁹/L and any measurable lymph node ≥ 5 cm were hospitalised to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up phase.
In 168 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg in studies M13-982 and M14-032, the rate of TLS was 2.4%. 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 micromol/L, calcium < 1.75 mmol/L, or phosphorus > 1.5 mmol/L; or were reported as TLS events) and occurred in patients who had a lymph node(s) ≥ 5 cm and/or ALC ≥ 25 x 10⁹/L. All events resolved within 5 days. 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.

Venclexta in combination with rituximab.

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

Venclexta in combination with obinutuzumab.

In the open-label, randomised phase 3 study (CLL14), the incidence of TLS (according to Howard criteria) was 1% (3/212) in patients treated with venetoclax + obinutuzumab (see Section 4.4 Special Warnings and Precautions for Use, Tumour lysis syndrome). All three events of TLS resolved and did not lead to withdrawal from the study. Obinutuzumab administration was delayed in two cases in response to the TLS events. In the open-label, randomised phase 3 study (CLL13), the incidence of TLS (according to Cairo-Bishop criteria) was 11% (25/228).

Venclexta in combination with ibrutinib.

In the open-label, randomized phase 3 study (GLOW), no adverse event of TLS was observed.
In the single-arm phase 3 study (CAPTIVATE), the incidence of laboratory TLS was 0.3% (1/323), reported in the MRD-guided cohort.
Acute myeloid leukaemia.

Venclexta in combination with azacitidine (VIALE-A) and Venclexta in combination with low-dose cytarabine (VIALE-C).

In the randomised, phase 3 study (VIALE-A) with venetoclax in combination with azacitidine, the incidence of TLS was 1.1% (3/283, 1 clinical TLS) and in the phase 3 study (VIALE-C) the incidence of TLS was 5.6% (8/142, 4 clinical TLS, 2 of which were fatal). The studies required reduction of white blood cell count to < 25 x 10⁹/L prior to venetoclax initiation and a dose ramp-up schedule in addition to standard prophylaxis and monitoring measures (see Section 4.2 Dose and Method of Administration, Dose modifications based on adverse reactions). All cases of TLS occurred during dose ramp-up.

Neutropenia.

Neutropenia is an identified risk associated with Venclexta treatment and occurs very commonly.
Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Venclexta in combination with rituximab.

In the MURANO study (venetoclax + rituximab versus bendamustine + rituximab for the treatment of patients with CLL), neutropenia of any grade was reported in 61%, and led to venetoclax interruption for 43% and discontinuation for 3% of patients in the venetoclax + rituximab arm. Grade 3 and grade 4 neutropenia were reported in 32% and 26% of venetoclax-treated patients, respectively. The median duration of grade 3 or 4 neutropenia was 8 days (range: 1-712 days). Clinical complications of neutropenia, including febrile neutropenia, grade ≥ 3 and serious infections were reported less frequently in the venetoclax + rituximab arm compared to the bendamustine + rituximab arm: febrile neutropenia 4% versus 10%, grade ≥ 3 infections 18% versus 23% and serious infections 21% versus 24% (see Section 4.8 Adverse Effects (Undesirable Effects), Serious infection).

Venclexta in combination with ibrutinib.

In the venetoclax + ibrutinib arm in the GLOW study, neutropenia (all grades) was reported in 42% of patients; grade 3 or 4 neutropenia was reported in 35% of patients. Nineteen percent experienced dose interruption and 8% had dose reduction due to neutropenia. In the venetoclax + ibrutinib arm versus the obinutuzumab + chlorambucil arm, respectively, the following were reported: febrile neutropenia 2% versus 3%, grade ≥ 3 infections 7% versus 9%, and serious infections 12% versus 9%.
In the CAPTIVATE study, neutropenia (all grades) was reported in 47% of patients in the venetoclax + ibrutinib arm; grade 3 or 4 neutropenia was reported in 37% of patients. Fourteen percent experienced dose interruption, 4% had dose reduction and 1 patient (0.3%) discontinued venetoclax due to neutropenia. Febrile neutropenia was reported in 1%, grade ≥ 3 infections in 8%, and serious infections in 8% of patients.

Venclexta in combination with obinutuzumab.

In the CLL14 study, neutropenia (all grades) was reported in 58% of patients in the venetoclax + obinutuzumab arm. Forty-one percent experienced dose interruption, 13% had dose reduction and 2% discontinued venetoclax due to neutropenia. Grade 3 neutropenia was reported in 25% of patients and grade 4 neutropenia in 28% of patients. The median duration of grade 3 or 4 neutropenia was 22 days (range: 2 to 363 days). The following complications of neutropenia were reported in the venetoclax + obinutuzumab arm versus the obinutuzumab + chlorambucil arm, respectively: febrile neutropenia 6% versus 4%, grade ≥ 3 infections 19% versus 16%, and serious infections 19% versus 14% (see Section 4.8 Adverse Effects (Undesirable Effects), Serious infection).
Acute myeloid leukaemia.

Venclexta in combination with azacitidine.

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

Venclexta in combination with low-dose cytarabine.

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

Serious infection.

Serious infection is an identified risk associated with Venclexta treatment.

Venclexta in combination with rituximab.

The most commonly reported serious infection in the venetoclax + rituximab treated patients was pneumonia (8%).

Venclexta in combination with obinutuzumab.

There were 56 events of serious infection, including 8 with fatal outcome, in 40/212 patients treated with venetoclax + obinutuzumab compared to 44 serious infection events, including 3 with fatal outcome, in 30/214 patients treated with chlorambucil + obinutuzumab. Of the 52/56 serious events in the patients treated with venetoclax + obinutuzumab for which neutrophil counts at the time of onset of the serious infection were available, 8/52 events occurred in the setting of neutropenia. Some serious infections occurred some time after completion of venetoclax treatment.

Venclexta as monotherapy.

The most frequently reported serious adverse reactions related to infection were pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). There have been 2 reports of death from septic shock occurring in the absence of disease progression and within 30 days of venetoclax treatment.

4.9 Overdose

Daily doses of up to 1200 mg of Venclexta have been evaluated in clinical trials. There has been no experience with overdose in clinical trials. If an overdose is suspected, treatment should consist of general supportive measures.
For information on the management of overdose in Australia contact the Poison Information Centre on 13 11 26.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Venetoclax is an orally bioavailable small molecule inhibitor of B-cell lymphoma (BCL)-2, an antiapoptotic protein. Overexpression of BCL-2 has been demonstrated in chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) cells, as well as various other haematological and solid tumour malignancies, and has been implicated in resistance to certain therapeutic agents. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing proapoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilisation, the release of cytochrome c from mitochondria and the activation of caspases. In nonclinical studies, venetoclax demonstrated cytotoxic activity in tumour cells that overexpress BCL-2.

Cardiac electrophysiology.

The effect of multiple doses of Venclexta up to 1200 mg once daily on the QTc interval was evaluated in an open label, single arm study in 176 patients with previously treated CLL or non-Hodgkin lymphoma (NHL). Venclexta had no effect on QTc interval and there was no relationship between venetoclax exposure and change in QTc interval.

Clinical trials.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Venclexta in combination with obinutuzumab.

CLL14.

CLL14 was a randomised (1:1), multicentre, open label phase 3 study that evaluated the efficacy and safety of Venclexta in combination with obinutuzumab versus obinutuzumab in combination with chlorambucil for previously untreated CLL in patients with coexisting medical conditions CIRS score > 6 or CrCl < 70 mL/min). The trial required hepatic transaminases and total bilirubin ≤ 2 times upper limit of normal and excluded patients with Richter's transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system.
Patients in the study were assessed for risk of TLS and received prophylaxis and monitoring accordingly prior to obinutuzumab administration and during Venclexta ramp-up. All patients received obinutuzumab at 1000 mg on cycle 1 day 1 (the first dose was split as 100 mg and 900 mg on days 1 and 2), and 1000 mg doses on days 8 and 15 of cycle 1, and on day 1 of each subsequent cycle, for a total of 6 cycles. On day 22 of cycle 1, patients in the venetoclax + obinutuzumab arm began the 5-week Venclexta ramp-up schedule (see Section 4.2 Dose and Method of Administration). After completing the ramp-up schedule on cycle 2 day 28, patients received Venclexta 400 mg once daily from cycle 3 day 1 until the last day of cycle 12. Patients randomised to the obinutuzumab + chlorambucil arm received 0.5 mg/kg oral chlorambucil on day 1 and day 15 of cycles 1 to 12, in the absence of disease progression or unacceptable toxicity. Each cycle was 28 days. Following completion of 12 cycles of Venclexta, patients continued to be followed for disease progression and overall survival.
Baseline demographic and disease characteristics were similar between the study arms (Table 17).

At baseline, the median lymphocyte count was 55 x 10⁹ cells/L in both study arms. On cycle 1 day 15, the median count decreased to 1.03 x 10⁹ cells/L (range 0.2-43.4 x 10⁹ cells/L) in the obinutuzumab + chlorambucil arm compared with 1.27 x 10⁹ cells/L (range 0.2-83.7 x 10⁹ cells/L) in the venetoclax + obinutuzumab arm.
The median follow-up at the time of analysis was 28 months (range: 0 to 36 months).
The primary endpoint was progression-free survival (PFS) as assessed by investigators using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).
Efficacy results for CLL14 are shown in Table 18.

At the time of analysis, median overall survival (OS) had not been reached, with fewer than 10% of patients experiencing an event. The median duration of follow-up for OS was 28 months.
Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was < 1 CLL cell per 10⁴ leukocytes. Rates of MRD negativity 3 months after the completion of treatment regardless of response and in patients with CR/CRi are shown in Table 19. At this assessment, 134 patients in the venetoclax + obinutuzumab arm who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 122 patients (91%) were MRD negative in both peripheral blood and bone marrow.

Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 58% (126/216) in patients treated with venetoclax + obinutuzumab and 9% (20/216) in patients treated with obinutuzumab + chlorambucil.
In paired samples, the concordance of MRD negativity between peripheral blood and bone marrow samples at end of treatment was 91% in the venetoclax + obinutuzumab arm and 58% in the obinutuzumab + chlorambucil arm.

65-month follow-up.

Efficacy was assessed after a median follow-up of 65 months (see Table 20).

The Kaplan-Meier curve for investigator-assessed PFS is shown in Figure 1.

The PFS benefit with venetoclax + obinutuzumab versus obinutuzumab + chlorambucil treatment was observed across all subgroups of patients evaluated (Figure 2).

CLL13.

Study CLL13 identified in the literature (Eichhorst et al. 2023) was a randomised phase 3 multicentre open-label study that enrolled patients with previously untreated CLL with a low burden of coexisting conditions and without 17p deletion or TP53 mutation to receive venetoclax in combination with obinutuzumab (N=229) or chemo-immunotherapy (either fludarabine, cyclophosphamide, rituximab [FCR] or bendamustine and rituximab [BR]) (N=229). Additional treatment arms assessed in CLL13 were venetoclax in combination with rituximab (N=237) or venetoclax in combination with obinutuzumab and ibrutinib (N=231). Patients had a CIRS score ≤ 6 and CrCl ≥ 70 mL/min. The treatment regimen of venetoclax + obinutuzumab in CLL13 was similar to that of CLL14 study.
The median follow-up time at the data cutoff was 38.8 months (interquartile range: 32.7 to 46.1 months).
The primary endpoints were undetectable minimal residual disease in peripheral blood at month 15 assessed using flow cytometry, and progression-free survival assessed by investigators. Efficacy results for the venetoclax + obinutuzumab and chemo-immunotherapy arms in CLL13 are shown in Table 21.

Study GP28331.

Study GP28331 was a multicentre, open-label, non-randomised study of venetoclax administered in combination with obinutuzumab that included 32 patients with previously untreated CLL. Twenty-two patients had a baseline CrCl ≥ 70 mL/min and a baseline ECOG of 0 or 1, and were therefore eligible to receive chemo-immunotherapy (e.g. fludarabine, cyclophosphamide, rituximab [FCR] or bendamustine and rituximab [BR]) as treatment. All 22 patients responded and 16 patients (73%) achieved a CR/CRi (investigator-assessed) with a median duration of follow-up of 26.7 months (range: 16 to 39 months). The 24-month PFS rate was 86% (95% CI: 72.02 to 100.00).
Venclexta in combination with ibrutinib.

GLOW (Study CLL3011).

A randomised, open-label, Phase 3 study of venetoclax in combination with ibrutinib versus chlorambucil in combination with obinutuzumab, was conducted in patients with previously untreated CLL or SLL who were 65 years or older, and adult patients < 65 years of age with a CIRS score > 6 or CrCL ≥ 30 to < 70 mL/min. Patients with 17p deletion or known TP53 mutations were excluded.
Patients (n = 211) were randomised 1:1 to receive either venetoclax in combination with ibrutinib or chlorambucil in combination with obinutuzumab. Patients in the venetoclax + ibrutinib arm received single agent ibrutinib for 3 cycles followed by venetoclax in combination with ibrutinib for 12 cycles (including 5-week dose ramp up). Each cycle was 28 days. Ibrutinib was administered at a dose of 420 mg daily. Venetoclax was administered according to the 5-week dose ramp-up, then at the recommended daily dose of 400 mg (see Section 4.2 Dose and Method of Administration). Patients randomised to the chlorambucil + obinutuzumab arm received treatment for 6 cycles. Obinutuzumab was administered at a dose of 1000 mg on Days 1, 8 and 15 in Cycle 1. In Cycles 2 to 6, 1000 mg obinutuzumab was given on Day 1. Chlorambucil was administered at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles = 1 to 6. Patients with confirmed progression by IWCLL criteria after completion of either fixed-duration regimen could be treated with single-agent ibrutinib.
The median age was 71 years (range, 47 to 93 years), 58% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (35%), 1 (53%), or 2 (12%). The trial enrolled 197 patients with CLL and 14 patients with SLL. At baseline, 18% of patients presented with CLL/SLL with 11q deletion and 52% with unmutated IgHV. The most common reasons for initiating CLL therapy included: constitutional symptoms (59%), progressive marrow failure (48%), lymphadenopathy (36%), splenomegaly (28%) and progressive lymphocytosis (19%). At baseline assessment for risk of TLS, 25% of patients had high tumour burden. After 3 cycles of single-agent ibrutinib lead-in therapy, 2% of patients had high tumour burden. High tumour burden was defined as any lymph node ≥ 10 cm; or any lymph node ≥ 5 cm and absolute lymphocyte count ≥ 25 x 10⁹/L.
With a median follow-up time on study of 28 months, efficacy results for GLOW assessed by an IRC according to IWCLL criteria are shown in Table 22, the Kaplan-Meier curve for PFS is shown in Figure 3, and rates of MRD negativity are shown in Table 23.

Across the high-risk CLL/SLL population (n = 123), including TP53 mutation (n = 9), 11q deletion (n = 38), or unmutated IgHV (n = 109), the treatment effect of venetoclax + ibrutinib was consistent, with a PFS HR of 0.23 [95% CI (0.13, 0.41)].

Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 49.1% (52/106) by next-generation sequencing (NGS) assay and 54.7% (58/106) by flow cytometry in patients treated with venetoclax + ibrutinib and, at the corresponding time point, was 12.4% (13/105) by NGS assay and 16.2% (17/105) by flow cytometry in patients treated with chlorambucil + obinutuzumab.
TLS was reported in 6 patients treated with chlorambucil + obinutuzumab and no TLS was reported in venetoclax in combination with ibrutinib as the study protocol included a specific TLS management strategy.
With a median follow-up of 46.1 months, 15 (out of 106, 14.2%) death events were observed in the venetoclax + ibrutinib arm versus 30 (out of 105, 28.6%) death events in the chlorambucil + obinutuzumab arm. This corresponds to a HR of 0.487 (95% CI: 0.262, 0.907) and a nominal p = 0.0205.

CAPTIVATE (Study PCYC-1142-CA).

A Phase 2, multi-centre, 2-cohort study assessing both MRD-guided discontinuation and fixed-duration therapy with venetoclax in combination with ibrutinib, was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL. The study enrolled 323 patients, of these, 159 patients were enrolled to fixed-duration therapy consisting of 3 cycles of single agent ibrutinib followed by venetoclax in combination with ibrutinib for 12 cycles (including 5 week dose ramp-up). Each cycle was 28 days. Ibrutinib was administered at a dose of 420 mg daily. Venetoclax was administered according to the 5 week dose ramp-up, then at the recommended daily dose of 400 mg (see Section 4.2 Dose and Method of Administration). Patients with confirmed progression by IWCLL criteria after completion of the fixed duration regimen could be retreated with single-agent ibrutinib, and 9 patients received this treatment.
The median age was 60 years (range, 33 to 71 years), 67% were male, and 92% were white. All patients had a baseline ECOG performance status of 0 (69%) or 1 (31%). The trial enrolled 146 patients with CLL and 13 patients with SLL. At baseline, 13% of patients had CLL/SLL with 17p deletion, 18% with 11q deletion, 17% with 17p deletion/TP53 mutation, 56% with unmutated IgHV and 19% with complex karyotype. The most common reasons for initiating CLL therapy included: lymphadenopathy (65%), progressive lymphocytosis (51%), splenomegaly (30%), fatigue (24%), progressive marrow failure demonstrated by anaemia and/or thrombocytopenia (23%), and night sweats (21%). At baseline assessment for risk of TLS, 21% of patients had high tumour burden. After 3 cycles of single-agent ibrutinib lead-in therapy, 1% of patients had high tumour burden. High tumour burden was defined as any lymph node ≥ 10 cm, or any lymph node ≥ 5 cm and absolute lymphocyte count ≥ 25 x 10⁹/L.
With a median follow-up time of 28 months, efficacy results for CAPTIVATE are shown in Table 24, and rates of MRD negativity are shown in Table 25.

At 3 months post-treatment in the fixed-duration cohort, 84 patients who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 76 patients (90%) were MRD negative in both peripheral blood and bone marrow.
In the fixed-duration cohort, no TLS was reported in patients treated with venetoclax in combination with ibrutinib.

CLL/SLL with 17p deletion/TP53 in CAPTIVATE.

In patients with 17p deletion/TP53 mutation (n = 27) the overall response rate based on IRC assessment was 96.3%; complete response rate was 55.6% and the median duration of complete response was not reached (range, 4.3 to 22.6 months). The MRD negativity rate in patients with 17p deletion/TP53 mutation 3 months after completion of treatment in bone marrow and peripheral blood was 40.7% and 59.3%, respectively.
Venclexta in combination with rituximab.

MURANO.

MURANO was a randomised (1:1), multicentre, open label phase 3 study that evaluated the efficacy and safety of Venclexta in combination with rituximab versus bendamustine in combination with rituximab in patients with CLL who had received at least one line of prior therapy. Patients in the venetoclax + rituximab arm completed the 5-week ramp-up schedule (see Section 4.2 Dose and Method of Administration) and were planned to receive 400 mg Venclexta daily for a maximum of 2 years in the absence of disease progression or unacceptable toxicity. Rituximab was initiated after the 5-week ramp-up at 375 mg/m² for cycle 1 and 500 mg/m² for cycles 2-6. Each cycle was 28 days. Patients randomised to bendamustine + rituximab received bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles and rituximab at the above described dose and schedule. Following completion of 24 months of venetoclax + rituximab regimen, patients continued to be followed for disease progression and overall survival.
A total of 389 patients were randomised; 194 to the venetoclax + rituximab arm and 195 to the bendamustine + rituximab arm. Table 26 shows the baseline demographic and disease characteristics were similar between the venetoclax + rituximab and bendamustine + rituximab arms.

The median survival follow-up at the time of analysis was 23.8 months (range: 0.0 to 37.4 months).
The primary endpoint was progression-free survival (PFS) as assessed by investigators using the IWCLL updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).
Efficacy results for MURANO are shown in Table 27.

At the time of primary analysis (data cutoff date 8 May 2017), 65 patients completed the 24 month venetoclax + rituximab treatment regimen without progression and 78 patients were still receiving venetoclax (+18 months of treatment). Of the 65 patients who remained progression free at 24 months, only 2 patients progressed after treatment completion. Twelve patients had a 3-month follow-up visit and remained progression free. Of the 12 patients, 5 were also assessed at 6-month follow-up and remained progression free.
Minimal residual disease was evaluated using ASO-PCR and/or flow cytometry. The cutoff for a negative status was less than one CLL cell per 10⁴ leukocytes in the sample. MRD data were available in peripheral blood in nearly all patients (187/194 in the venetoclax + rituximab arm versus 179/195 in the bendamustine + rituximab arm) and in a subset of patients for bone marrow (74/194 in the venetoclax + rituximab arm versus 41/195 in the bendamustine + rituximab arm). Peripheral blood MRD negativity rates, assessed at any time during the study, were observed in 84% (162/194) of patients in the venetoclax + rituximab arm versus 23% (45/195) of patients in the bendamustine + rituximab arm. Bone marrow MRD negativity rates were 27% (53/194 patients) in the venetoclax + rituximab arm versus 2% (3/195 patients) in the bendamustine + rituximab arm. At the 9-month response assessment, MRD negativity in the peripheral blood was 62% in the venetoclax + rituximab arm versus 13% in the bendamustine + rituximab arm and this rate was maintained in the venetoclax + rituximab arm for at least an additional 9 months (60% in venetoclax + rituximab versus 5% in bendamustine + rituximab), the last visit for which complete data were available prior to the clinical cutoff date.

59-month follow-up.

Efficacy was assessed after a median follow‑up of 59.2 months (data cut-off date 8 May 2020). Efficacy results for the MURANO 59-month follow-up are presented in Table 28.

In total, 130 patients in the venetoclax + rituximab arm completed 2 years of Venclexta treatment without progression. For these patients, the 3-year PFS estimate post-treatment was 51% [95% CI: 40.2, 61.9].
The Kaplan-Meier curve for investigator-assessed PFS is shown in Figure 4.

The Kaplan-Meier curve for overall survival is shown in Figure 5.

The observed PFS benefit of venetoclax + rituximab compared with bendamustine + rituximab was consistently observed across all subgroups of patients evaluated, including high-risk patients with deletion 17p/TP53 mutation and/or unmutated IgVH (Figure 6).

Venclexta as monotherapy. The safety and efficacy of Venclexta were established in three open-label, multicentre clinical trials of patients with CLL or SLL who had received at least one prior therapy, including those with deletion of the p13 locus on chromosome 17 (17p deletion).

Study M13-982.

Study M13-982 was a multicentre, single arm open label trial of 107 patients with previously treated CLL with 17p deletion. Table 29 summarises the baseline demographic and disease characteristics of the study population.

Among the patients, 37% (34/91) were fludarabine refractory, 81% (30/37) had unmutated IgVH, and 24% (19/80) had 11q deletion.
In the study, patients with 17p deletion were identified using Vysis CLL FISH Probe Kit. Patients received Venclexta via a weekly ramp-up schedule starting at 20 mg and titrating to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of Venclexta orally once daily until disease progression or unacceptable toxicity. The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months).
The primary efficacy endpoint was overall response rate (ORR) as assessed by an IRC using the IWCLL updated NCI-WG guidelines (2008). Efficacy results for study M13-982 are shown in Table 30.

Based on a later data cutoff (15 June 2017), which included an additional 51 patients enrolled in a safety expansion cohort, and investigator-assessed efficacy (N = 158), the median duration of response (DOR) was 36.2 months (95% CI: 27.2, NA). The median duration of progression-free survival (mPFS) was 28.2 months (95% CI: 23.4, 37.0).
Minimal residual disease was evaluated using flow cytometry in 45 of 107 patients who achieved complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) with limited remaining disease with Venclexta treatment. The cut-off for a negative status was one CLL cell per 10⁴ leukocytes in the sample (i.e. an MRD value of < 10^-4 was considered MRD negative). Seventeen percent (18/107) of patients were MRD negative in the peripheral blood, including six patients who were also MRD negative in the bone marrow.

Study M12-175.

Study M12-175 was a multicentre, open label trial that enrolled patients with previously treated CLL or SLL, including those with 17p deletion. Efficacy was evaluated in 67 patients (59 with CLL, 8 with SLL) who had received a daily dose of 400 mg of Venclexta following a ramp-up schedule. Patients continued to receive 400 mg of Venclexta monotherapy orally once daily until disease progression or unacceptable toxicity. The median time on treatment at the time of evaluation was 22.1 months (range: 0.5-50.1 months). Table 31 summarises the baseline demographic and disease characteristics of the study population.

Among the patients, 70% were fludarabine refractory, 67% (22/33) had unmutated IgVH, 31% (18/58) had 11q deletion, and 24% (14/58) had 17p deletion.
Overall response rate and duration of response were evaluated by both investigators and an IRC according to the IWCLL NCI-WG criteria. Efficacy results are shown in Table 32.

For the 8 patients with SLL, the investigator-assessed ORR was 100%.

Study M14-032.

Study M14-032 was an open label, multicentre, study that evaluated the efficacy of venetoclax in patients with CLL who had been previously treated with and progressed on or after ibrutinib (Arm A) or idelalisib (Arm B). Patients received a daily dose of 400 mg of venetoclax following the ramp-up schedule. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed.
Efficacy was evaluated by investigators and an IRC according to IWCLL updated NCI WG guidelines (2008). Response assessments were performed at 8 weeks, 24 weeks, and every 12 weeks thereafter for the 64 patients in the main cohort, while the patients enrolled in the expansion had disease assessment at weeks 12 and 36.
A total of 127 patients were enrolled in the study, which included 64 patients in the main cohort (43 with prior ibrutinib, 21 with prior idelalisib) and 63 patients in an expansion cohort (48 with prior ibrutinib, 15 with prior idelalisib). Table 33 summarises the baseline demographic and disease characteristics of the study population.

Efficacy data are presented with data cutoff date of 26 July 2017. Investigator-assessment of disease responses to venetoclax treatment are available for all 127 subjects (64 in the main cohort and 63 in the expansion cohort). The IRC assessments of disease responses are available for 123 of the 127 subjects.
Efficacy results for 127 patients assessed by investigator and 127 patients assessed by IRC at the same time points are shown in Table 34.

The median duration of treatment with venetoclax for 127 patients was 14.3 months (range: 0.1 to 31.4 months).
The MRD negativity rate in peripheral blood for all 127 patients was 25.2% (32/127), including 8 patients who achieved MRD negativity in bone marrow.

Acute myeloid leukaemia.

Venclexta was studied in adult patients with newly diagnosed AML who were ≥ 75 years, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CrCl < 45 mL/min, or other comorbidity.
Venclexta in combination with azacitidine.

VIALE-A.

VIALE-A was a randomised (2:1), double-blind, placebo controlled, multicentre, phase 3 study that evaluated the efficacy and safety of Venclexta in combination with azacitidine versus placebo in combination with azacitidine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy.
Patients in VIALE-A completed the 3-day ramp-up schedule to a final 400 mg once daily dose during the first 28-day cycle of treatment (see Section 4.2 Dose and Method of Administration) and received Venclexta 400 mg orally once daily thereafter in subsequent cycles. Azacitidine at 75 mg/m² was administered either intravenously or subcutaneously on days 1-7 of each 28-day cycle beginning on cycle 1 day 1. Placebo orally once daily was administered on day 1-28 plus azacitidine at 75 mg/m² on day 1-7 of each 28-day cycle beginning on cycle 1 day 1. During the ramp-up, patients received TLS prophylaxis and were hospitalised for monitoring.
Once bone marrow assessment confirmed a remission, defined as less than 5% leukaemia blasts with cytopenia following cycle 1 treatment, Venclexta or placebo was interrupted up to 14 days or until ANC ≥ 500/microlitre and platelet count ≥ 50 x 10³/microlitre. For patients with resistant disease at the end of cycle 1, a bone marrow assessment was performed after cycle 2 or 3 and as clinically indicated. Azacitidine was resumed on the same day as Venclexta or placebo following interruption (see Section 4.2 Dose and Method of Administration, Dose modifications based on adverse reactions). Azacitidine dose reduction was implemented in the clinical trial for management of haematological toxicity. Patients continued to receive treatment cycles until disease progression or unacceptable toxicity.
A total of 431 patients were randomised: 286 to the venetoclax + azacitidine arm and 145 to the placebo + azacitidine arm. Baseline demographic and disease characteristics were similar between the venetoclax + azacitidine and placebo + azacitidine arms. The baseline demographic and disease characteristic are shown in Table 35.

The dual primary endpoints of the study were overall survival (OS) measured from the date of randomisation to death from any cause and composite complete remission rate (complete remission + complete remission with incomplete blood count recovery; CR+CRi). The overall median follow-up at the time of analysis was approximately 20.5 months (range: < 0.1 to 30.7 months).
Venetoclax + azacitidine demonstrated a 34% reduction in the risk of death compared with placebo + azacitidine (p < 0.001). The efficacy results are presented in Tables 36 and 37. The Kaplan-Meier curve for OS is shown in Figure 7.

Key secondary efficacy endpoints are presented in Table 37.

Of patients with FLT3 mutations, the CR+CRh rates were 66% (19/29; [95% CI: 46, 82]) and 18% (4/22; [95% CI: 5, 40]) in the venetoclax + azacitidine and placebo + azacitidine arms, respectively (Fisher's exact test p = 0.001). Of patients with FLT3 mutations, 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 (Fisher's exact test p = 0.021).
Of patients with IDH1/IDH2 mutations, the CR+CRh rates were 72% (44/61; [95% CI: 59, 83]) and 7% (2/28; [95% CI: 1, 24]) in the venetoclax + azacitidine and placebo + azacitidine arms, respectively (Fisher's exact test p < 0.001). Of patients with IDH1/IDH2 mutations, the CR+CRi rates were 75% (46/61; [95% CI: 63, 86]) and 11% (3/28; [95% CI: 2, 28]) in the venetoclax + azacitidine and placebo + azacitidine arms, respectively (Fisher's exact test p < 0.001).
Of the patients who were red blood cell transfusion dependent at baseline and treated with venetoclax + azacitidine, 49% (71/144) became transfusion independent. Of the patients who were platelet transfusion dependent at baseline and treated with venetoclax + azacitidine, 50% (34/68) became transfusion independent.
The median time to first response of CR or CRi was 1.3 months (range: 0.6 to 9.9 months) with venetoclax + azacitidine treatment. The median time to best response of CR or CRi was 2.3 months (range: 0.6 to 24.5 months).

Study M14-358.

Study M14-358 was a non-randomised phase 1b study of Venclexta in combination with azacitidine (N = 84) in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. Patients received Venclexta via ramp-up to a final 400 mg once daily dose. The administration of azacitidine in M14-358 was similar to that of VIALE-A randomised study.
The median follow-up was 28.9 months (range: 0.4 to 42.0 months) for Venclexta in combination with azacitidine.
The median age of patients treated with venetoclax + azacitidine was 75 years (range: 61-90 years), 91% were white, 61% male, and 69% had ECOG score 0 or 1. The CR+CRi rate was 71% (95% CI: 61, 81) for patients treated with Venclexta in combination with azacitidine. Median overall survival for patients treated with Venclexta in combination with azacitidine was 16.4 months (95% CI: 11.3, 24.5).
Venclexta in combination with low-dose cytarabine.

VIALE-C.

VIALE-C was a randomised (2:1), double-blind, placebo-controlled, multicentre, phase 3 study (M16-043) that evaluated the efficacy and safety of Venclexta in combination with low-dose cytarabine versus placebo in combination with low-dose cytarabine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy.
Patients in VIALE-C completed the 4-day ramp-up schedule to a final 600 mg once daily dose during the first 28-day cycle of treatment (see Section 4.2 Dose and Method of Administration) and received Venclexta 600 mg orally once daily thereafter in subsequent cycles. Cytarabine 20 mg/m² was administered subcutaneously (SC) once daily on days 1-10 of each 28-day cycle beginning on cycle 1 day 1. Once daily oral placebo was administered on days 1-28 plus cytarabine 20 mg/m² subcutaneously once daily on days 1-10. During the ramp-up, patients received TLS prophylaxis and were hospitalised for monitoring.
Once bone marrow assessment confirmed a remission, as defined as less than 5% leukaemia blasts with cytopenia following cycle 1 treatment, Venclexta or placebo was interrupted up to 14 days or until ANC ≥ 500/microlitre and platelet count ≥ 25 x 10³/microlitre. For patients with resistant disease at the end of cycle 1, a bone marrow assessment was performed after cycle 2 or 3 and as clinically indicated. Patients continued to receive treatment cycles until disease progression or unacceptable toxicity. Dose reduction for low-dose cytarabine was not implemented in the clinical trial.
Baseline demographic and disease characteristics were similar between the venetoclax + low-dose cytarabine and placebo + low-dose cytarabine arms. The baseline demographic and disease characteristic are shown in Table 38.

At the time of the primary analysis for OS, patients had a median follow-up of 12 months (range: 0.1 to 17.6 months). The median OS in the venetoclax + low-dose cytarabine arm was 7.2 months (95% CI: 5.6, 10.1) and in the placebo with low-dose cytarabine arm was 4.1 months (95% CI: 3.1, 8.8). The hazard ratio was 0.75 (95% CI: 0.52, 1.07; p = 0.114). The Kaplan-Meier curve for OS is shown in Figure 8.

In an additional analysis for OS at which time patients had a median follow-up of 17.5 months (range: 0.1 to 23.5 months). The median OS in the venetoclax + low-dose cytarabine arm was 8.4 months (95% CI: 5.9, 10.1) and in the placebo + low-dose cytarabine arm was 4.1 months (95% CI: 3.1, 8.1). The hazard ratio was 0.70 (95% CI: 0.50, 0.99). The Kaplan-Meier curve for OS with 6 additional months of follow up is shown in Figure 9.

Efficacy results for secondary endpoints from the primary analysis are shown in Table 39.

The CR+CRi rate by initiation of cycle 2 for venetoclax + low-dose cytarabine was 34% (95% CI: 27, 43) and for placebo + low-dose cytarabine was 3% (95% CI: 0.4, 10). The median time to first response of CR+CRi was 1.1 months (range: 0.8 to 4.7 months) with venetoclax + low-dose cytarabine treatment. The median time to best response of CR+CRi was 1.2 months (range: 0.8 to 5.9 months).
Minimal residual disease response was defined as less than one AML cell per 103 leukocytes in the bone marrow. For the patients who had MRD assessment (113 patients in venetoclax + low dose cytarabine arm and 44 in placebo + low dose cytarabine arm), the median MRD value (%) was lower in the venetoclax arm when compared to the placebo arm (0.42 and 7.45, respectively). A higher number of patients had achieved CR + CRi and MRD response on venetoclax arm compared to placebo arm: 8 patients (6%) (95% CI: 2, 11) vs 1 patient (1%) (95% CI: 0, 8), respectively.
The median event-free survival for venetoclax + low-dose cytarabine was 4.7 months (95% CI, 3.7, 6.4) compared with 2.0 months (95% CI, 1.6, 3.1) for placebo + low-dose cytarabine with HR (95% CI) of 0.58 (0.42, 0.82).

Study M14-387.

Study M14-387 was a non-randomised phase 1/2 study of Venclexta in combination with low-dose cytarabine (N = 82) in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. Patients received Venclexta via ramp-up to a final 600 mg once daily dose. The administration of low-dose cytarabine in M14-387 was similar to that of VIALE-C randomised study.
The median follow-up was 41.7 months (range: 0.3 to 54.0 months) for Venclexta in combination with low-dose cytarabine.
The median age of patients treated with venetoclax + low-dose cytarabine was 74 years (range: 63-90 years), 95% were white, 65% male, and 71% had ECOG score 0 or 1. The CR+CRi rate was 54% (95% CI: 42, 65) for patients treated with Venclexta in combination with low-dose cytarabine. Median overall survival for patients treated with Venclexta in combination with low-dose cytarabine was 9.7 months (95% CI: 5.7, 14.0).

5.2 Pharmacokinetic Properties

Absorption.

Following multiple oral administrations, the maximum plasma concentration of venetoclax was reached 5 to 8 hours after dosing. Venetoclax steady-state AUC increased proportionally over the dose range of 150-800 mg. Under low fat meal conditions, venetoclax mean (± standard deviation) steady-state C_max was 2.1 ± 1.1 microgram/mL and AUC_0-24h was 32.8 ± 16.9 microgram.h/mL at the 400 mg once daily dose, and 2.7 ± 1.6 micrograms/mL and 45.6 ± 30.6 micrograms.h/mL, respectively, at 600 mg/day.
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions. Venetoclax should be administered with a meal (see Section 4.2 Dose and Method of Administration).

Distribution.

Venetoclax is highly bound to human plasma protein with the unbound fraction in plasma < 0.01 across a concentration range of 1-30 micromoles (0.87-26 microgram/mL). The mean blood to plasma ratio is 0.57.
The population estimate for apparent volume of distribution (Vd_ss/F) of venetoclax ranges from 256-321 L in patients.

Metabolism.

In vitro studies demonstrated that venetoclax is predominantly metabolised by 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 studies.

In vitro studies indicated that venetoclax is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, CYP2D6 or CYP3A4 and not an inducer of CYP1A2, 2B6 or 3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of UGT1A1, CYP2C8 and CYP2C9 in vitro, but it is not predicted to cause clinically relevant inhibition of these enzymes due to high plasma protein binding. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7.
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro. Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K at clinically relevant concentrations.

Elimination.

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

Special populations.

Age, race, sex and weight.

Based on population pharmacokinetic analyses, age, race, sex and weight do not have an effect on venetoclax clearance.

Paediatric population (< 18 years).

The pharmacokinetics of Venclexta have not been evaluated in patients < 18 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Renal impairment.

Based on a population pharmacokinetic analysis that included 321 subjects with mild renal impairment (CrCl ≥ 60 and < 90 mL/min), 219 subjects with moderate renal impairment (CrCl ≥ 30 and < 60 mL/min), 6 subjects with severe renal impairment (CrCl ≥ 15 and < 30 mL/min) and 224 subjects with normal renal function (CrCl ≥ 90 mL/min), venetoclax exposures in subjects with mild, moderate or severe renal impairment are similar to those with normal renal function. The pharmacokinetics of venetoclax have not been studied in subjects with CrCl < 15 mL/min or subjects on dialysis (see Section 4.4 Special Warnings and Precautions for Use, Renal impairment).

Hepatic impairment.

Based on a population pharmacokinetic analysis that included 69 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 429 subjects with normal hepatic function, venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. The National Cancer Institute (NCI) Organ Dysfunction Working Group criteria for hepatic impairment were used in the analysis. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin > 1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin > 1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin > 3.0 ULN.
In a dedicated hepatic impairment study, venetoclax C_max and AUC in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment were similar to subjects with normal hepatic function. In subjects with severe (Child-Pugh C) hepatic impairment, the mean venetoclax C_max was similar to subjects with normal hepatic function but venetoclax AUC was 2.3- to 2.7 fold higher than subjects with normal hepatic function (see Section 4.4 Special Warnings and Precautions for Use, Hepatic impairment).

5.3 Preclinical Safety Data

Animal pharmacology and/or toxicology.

Toxicities observed in animal studies with venetoclax included dose-dependent reductions in lymphocytes and red blood cell mass. After cessation of dosing with venetoclax, red blood cell effects were reversible, whereas partial reversibility of lymphocytes was observed at the end of an 18-week recovery period. Both B- and T-cells were affected, but the most significant decreases occurred with B-cells.
Venetoclax also caused single-cell necrosis in various tissues, including the gallbladder and exocrine pancreas, with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery.
After approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment in the hair. No changes in the quality of the hair coat or skin were observed, nor in other pigmented tissues examined (e.g. the iris and the ocular fundus of the eye). Reversibility of the hair coat changes has not been assessed in dogs.
The M27 metabolite orally administered to mice had effects similar to those with venetoclax (decreased lymphocytes and red blood cell mass) but of lesser magnitude, consistent with its low pharmacologic activity in vitro.

Genotoxicity.

Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at a single oral dose up to 835 mg/kg (~5 times the clinical C_max at the maximum recommended dose of 600 mg/day). The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Venclexta 10 mg film-coated tablets contain the following inactive ingredients: copovidone, colloidal anhydrous silica, polysorbate 80, sodium stearylfumarate, calcium hydrogen phosphate, iron oxide yellow, polyvinyl alcohol, macrogol 3350, purified talc and titanium dioxide.
Venclexta 50 mg film-coated tablets contain the following inactive ingredients: copovidone, colloidal anhydrous silica, polysorbate 80, sodium stearylfumarate, calcium hydrogen phosphate, iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, purified talc, macrogol 3350 and titanium dioxide.
Venclexta 100 mg film-coated tablets contain the following inactive ingredients: copovidone, colloidal anhydrous silica, polysorbate 80, sodium stearylfumarate, calcium hydrogen phosphate, iron oxide yellow, polyvinyl alcohol, macrogol 3350, purified talc and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Venclexta is dispensed as follows, see Table 40.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)- N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino] phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy)benzamide.

Chemical structure.

Empirical formula: C₄₅H₅₀ClN₇O₇S.
Molecular weight: 868.44.

CAS number.

1257044-40-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Venclexta 10 mg Tablets

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