Consumer medicine information

Gazyva

Obinutuzumab

BRAND INFORMATION

Brand name

Gazyva

Active ingredient

Obinutuzumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Gazyva.

SUMMARY CMI

Gazyva®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Gazyva?

Gazyva contains the active ingredient obinutuzumab. Gazyva is used to:
- treat chronic lymphocytic leukaemia (CLL).
- treat follicular lymphoma (FL) either in patients who have not been treated before or in patients who are no longer responding to treatment with another medicine called rituximab.
- reduce the severity of cytokine release syndrome (CRS), a possible serious side effect of glofitamab treatment

For more information, see Section 1. Why am I using Gazyva? in the full CMI.

2. What should I know before I use Gazyva?

Do not use if you have ever had an allergic reaction to Gazyva or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Gazyva? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Gazyva and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Gazyva given?

Gazyva must be prepared by a healthcare professional and will be given in a hospital or clinic by a doctor or nurse. You will be given Gazyva by infusion into a vein (intravenous (IV) infusion). The number of infusions you will be given depends on why you are being given Gazyva and how you respond to the treatment. Before you receive Gazyva you will be given other medicines to help reduce the severity of possible infusion reactions. More instructions can be found in Section 4. How is Gazyva given? in the full CMI.

5. What should I know while using Gazyva?

Things you should do

  • Remind any doctor, dentist, nurse or pharmacist you visit that you are using Gazyva.
  • Tell your doctor or nurse immediately if you have any signs or symptoms of an infusion reaction or allergic reaction, or heart problems.
  • Tell your partner or caregiver you are receiving Gazyva and ask them to tell you if they notice any changes in your movement or behaviour. If they notice any changes you should tell your doctor about them immediately.
  • Tell your doctor if you become pregnant or intend to start a family while receiving Gazyva, if you intend to breast feed whilst receiving Gazyva, or if you intend to vaccinate your baby and were pregnant with your baby whilst receiving Gazyva.

Things you should not do

  • Do not stop your Gazyva treatment without talking to your doctor first.
  • Do not take any other medicines, whether they require a prescription or not without first telling your doctor or consulting with a pharmacist

Driving or using machines

  • Be careful driving or operating machinery until you know how Gazyva affects you.

For more information, see Section 5. What should I know while using Gazyva? in the full CMI.

6. Are there any side effects?

Serious side effects include reactions such as swelling of the face, lips, tongue, throat or other parts of the body, trouble breathing, wheezing or coughing. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Progressive Multifocal Leukoencephalopathy

Progressive Multifocal Leukoencephalopathy (PML) is a rare, serious brain infection that can cause severe disability or even death. PML is a rare side effect that can occur whilst receiving Gazyva. Tell your partner or caregiver you are receiving Gazyva and ask them to tell you if they notice any changes in your movement or behaviour. If they notice any changes you should tell your doctor about them immediately



FULL CMI

Gazyva®

Active ingredient(s): obinutuzumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using Gazyva. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Gazyva.

Where to find information in this leaflet:

1. Why am I using Gazyva?
2. What should I know before I use Gazyva?
3. What if I am taking other medicines?
4. How is Gazyva given?
5. What should I know while using Gazyva?
6. Are there any side effects?
7. Product details

1. Why am I using Gazyva?

Gazyva contains the active ingredient obinutuzumab. Gazyva belongs to a group of medicines known as anti-neoplastic (or anti-cancer) agents. There are many different classes of anti-neoplastic agents. Gazyva belongs to a class called monoclonal antibodies.

Monoclonal antibodies are proteins which specifically recognise and bind to other unique proteins in the body.

Gazyva is used to:

  • treat chronic lymphocytic leukaemia (CLL)
  • treat follicular lymphoma (FL) either in patients who have not been treated before or in patients who are no longer responding to treatment with another medicine called rituximab
  • reduce the severity of cytokine release syndrome (CRS), a possible serious side effect of glofitamab treatment

Gazyva recognises and attaches to a protein called CD20 which is found on the surface of white blood cells known as B lymphocytes. During the process of binding to the protein, the abnormal growth of the B lymphocytes is stopped. It is the abnormally growing B lymphocytes that are responsible for CLL and FL.

For CLL Gazyva is used with the chemotherapy medicine chlorambucil. For FL Gazyva is first given with chemotherapy medicines and then on its own.

Gazyva reduces the number of B lymphocytes before treatment with glofitamab, a medicine given to treat diffuse large b-cell lymphoma (DLBCL).

For further information about any other medicines used with Gazyva please ask your doctor, nurse or pharmacist for the Consumer Medicine Information (CMI) for these medicines.

2. What should I know before I use Gazyva?

Warnings

Do not use Gazyva if:

  • you are allergic to obinutuzumab, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • if you have had an allergic reaction to any other proteins that are of mouse origin
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin

Check with your doctor if:

  • you have an infection, or a history of a recurring or long-term infection such as hepatitis B
  • you are taking or have previously taken medicines which may affect your immune system, such as chemotherapy or immunosuppressive medicines
  • you are taking or have taken medicines which affect your immune system, you may have an increased risk of infections. There have been reports of a rare, serious brain infection called PML (progressive multifocal leukoencephalopathy) usually affecting people with a weakened immune system. Your chance of getting PML may be higher if you are treated with medicines that weaken the immune system, including Gazyva. PML can cause severe disability or even death.
  • you have a history of heart disease with:
    - cardiac arrhythmias (abnormal beating of the heart)
    - angina (chest pain)
    - heart failure or a recent heart attack
  • you are taking medicine to control blood pressure
  • you are taking medicine to prevent blood clots
  • you have pre-existing lung disease
  • you have kidney disease
  • you have liver disease
  • you intend to have or have had immunisation with any vaccine
  • you are allergic to any other medicines or any other substances such as foods, preservatives or dyes
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant.

It is not known whether Gazyva is harmful to an unborn baby. It is not recommended that you are given Gazyva while you are pregnant.

If you are of child bearing potential, it is recommended that you do not become pregnant for 18 months following the end of treatment with Gazyva.

If you are of child bearing potential, it is recommended that you use effective contraceptive methods during treatment and for up to 18 months following the end of treatment with Gazyva.

Breastfeeding

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if Gazyva passes into breast milk. It is recommended that you discontinue breast feeding while you are treated with Gazyva and for 18 months after your final infusion of Gazyva.

Use in children

The safety and efficacy of Gazyva in children and adolescents under 18 years of age have not been established.

3. What if I am taking other medicines?

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

As Gazyva may cause a temporary drop in your blood pressure, your doctor may advise you to temporarily stop taking your blood pressure medicine before you are given Gazyva.

Gazyva can reduce the number of platelets in your blood. Taking medicine to prevent blood clots while you are receiving Gazyva may further reduce the number of platelets. This may cause life-threatening bleeding. Your doctor will supervise you closely during treatment with Gazyva.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Gazyva.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Gazyva.

4. How is Gazyva given?

Follow all directions given to you by your doctor or nurse carefully.

They may differ from the information contained in this leaflet.

Gazyva must be prepared by a healthcare professional and will be given in a hospital or clinic by a doctor or nurse. Gazyva is given by infusion into a vein (intravenous (IV) infusion).

How much and when to take Gazyva

Your doctor will decide how many infusions you need and the duration of the infusions.

Your doctor may adjust your infusion depending on how well each one is tolerated.

You will be closely monitored during each infusion.

Before you receive Gazyva you will be given other medicines to help reduce the severity of possible infusion reactions.

For chronic lymphocytic leukaemia (CLL)

The first infusion: you will be given 100 mg of Gazyva by IV infusion over 4 hours.

The second infusion: if the first infusion was well tolerated, you will be given 900 mg of Gazyva by IV infusion, either on the same day as the first infusion or a day later.

Subsequent infusions: if the previous infusion was well tolerated, you will be given 1000 mg of Gazyva by IV infusion.

For follicular lymphoma (FL)

The first infusion: you will be given 1000 mg of Gazyva by IV infusion.

Subsequent infusions: if the first infusion was well tolerated, you will be given 1000 mg of Gazyva by IV infusion.

Maintenance treatment: if you respond to initial treatment your doctor may decide to continue your treatment with Gazyva.

You may receive Gazyva once every 2 months for up to 2 years.

For pre-treatment to reduce the severity of Cytokine Release Syndrome (CRS) induced by glofitamab

You will be given a single 1000 mg dose of Gazyva by IV infusion 7 days before your glofitamab treatment begins.

If you miss a dose

As Gazyva is given under the supervision of your doctor, you are unlikely to miss a dose. However, if you forget or miss your appointment to receive Gazyva, you should not wait until the next planned dose but make another appointment as soon as possible.

If you use too much Gazyva

As Gazyva is given under the supervision of your doctor, it is very unlikely that you will be given too much. However, if you experience any side effects after being given Gazyva, tell your doctor immediately.

5. What should I know while using Gazyva?

Things you should do

Tell your doctor or nurse immediately if you have any signs or symptoms of an infusion reaction or allergic reaction, or heart problems.

Some signs and symptoms can include:

  • swelling of your face, lips, tongue or throat with difficulty breathing
  • swelling of other parts of your body
  • shortness of breath, wheezing or trouble breathing
  • rash, itching or hives on the skin
  • feeling sick (nausea)
  • fever, chills
  • feeling tired
  • headache
  • chest pain
  • abnormal or irregular heartbeat

Tell your partner or caregiver you are receiving Gazyva and ask them to tell you if they notice any changes in your movement or behaviour. If they notice any changes you should tell your doctor about them immediately.

Your doctor may need to perform some tests and alter your treatment.

Tell all doctors, dentists, nurses and pharmacists who are treating you that you are receiving Gazyva.

Tell your doctor if you become pregnant or intend to start a family while receiving Gazyva, if you intend to breast feed whilst receiving Gazyva, or if you intend to vaccinate your baby and were pregnant with your baby whilst receiving Gazyva.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Your doctor will perform regular blood tests.

Things you should not do

Do not stop your Gazyva treatment without talking to your doctor first.

Tell your doctor if you feel that Gazyva is not helping your condition.

Do not take any other medicines, whether they require a prescription or not without first telling your doctor or consulting with a pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Gazyva affects you.

Gazyva is unlikely to cause any problems with your ability to drive or operate machinery. However if you get any signs or symptoms of an infusion reaction or allergic reaction, or heart problems, you should refrain from driving or operating machinery until the reaction stops.

Looking after your medicine

Gazyva will be stored in the pharmacy or on the hospital ward in a refrigerator at a temperature between 2°C and 8°C.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor or nurse as soon as possible if you do not feel well while you are receiving Gazyva.

If you are 65 years of age or older or suffer problems with your kidneys you may have an increased chance of getting side effects.

You may experience side effects during an infusion or after an infusion, these can be serious or less serious.

Serious side effects

Serious side effects

What to do

During an infusion:

  • swelling of your face, lips, tongue or throat with difficulty breathing
  • swelling of other parts of your body
  • shortness of breath, wheezing or trouble breathing
  • rash, itching or hives on the skin
  • vomiting or feeling sick (nausea)
  • fever, flushing or chills
  • diarrhoea
  • cough or throat irritation
  • feeling tired
  • headache
  • chest pain
  • dizziness or light headedness
  • abnormal or irregular heartbeat

Tell your doctor or nurse immediately if you notice any of these while receiving an infusion. These may be serious side effects.
You may need medical attention.

After an infusion:

  • swelling of your face, lips, tongue or throat with difficulty breathing
  • swelling of other parts of your body
  • shortness of breath, wheezing or trouble breathing
  • skin problems including rash, itchiness or hives, hardened or discoloured skin lesions which may increase in size
  • stomach cramps or pains
  • severe or bloody diarrhoea
  • nausea and vomiting including vomiting blood or material that looks like coffee grounds
  • fever, chills
  • severe coughing
  • abnormal or irregular heartbeat
  • chest pain
  • bleeding or bruising more than normal
  • blood clots
  • feeling dizzy or lightheaded
  • one or a combination of the following: confusion, disorientation or memory loss, changes in the way you move, walk or talk, decreased strength or progressive weakness in your body, blurred or loss of vision.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of these signs after an infusion. These may be serious side effects.
You may need medical attention.

Less serious side effects

Less serious side effects

What to do

After an infusion:

  • frequent infections such as fever, severe chills, respiratory infections (including pneumonia), shingles, mouth ulcers or urinary infections
  • pain in mouth or throat
  • runny or stuffy nose or stuffy chest
  • joint, bone or muscle pain
  • arm, leg or back pain
  • headache
  • diarrhoea, constipation, abdominal discomfort or pain, or haemorrhoids
  • urinary incontinence or pain
  • increased weight
  • persistent cough
  • hair loss
  • night sweats
  • itchy skin
  • red eye
  • sleeplessness and/or feeling tired
  • feeling depressed or anxious

Speak to your doctor if you have any of these less serious side effects and they worry you.

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

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Gazyva contains

Active ingredient

(main ingredient)

obinutuzumab.

Other ingredients

(inactive ingredients)

histidine

histidine hydrochloride monohydrate

trehalose dehydrate

poloxamer 188

Potential allergens

Refer to your healthcare professional for further advice

Do not take this medicine if you are allergic to any of these ingredients.

What Gazyva looks like

Gazyva is a clear, colourless to slightly brownish liquid. Gazyva is supplied as a single-dose glass vial containing 40 mL of solution for intravenous infusion (25 mg/mL). It is diluted before infusion into a vein. (AUST R 210562).

Who distributes Gazyva

Gazyva is distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney, NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950

https://medinfo.roche.com/au/en.html

Please check with your pharmacist for the latest Consumer Medicine Information (CMI).

This leaflet was prepared in May 2023.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Gazyva

Active ingredient

Obinutuzumab

Schedule

S4

 

1 Name of Medicine

Obinutuzumab.

2 Qualitative and Quantitative Composition

One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentration before dilution of 25 mg/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion.
Clear, colourless to slightly brownish.

4 Clinical Particulars

4.1 Therapeutic Indications

Chronic lymphocytic leukaemia.

Gazyva in combination with chlorambucil is indicated for the treatment of patients with previously untreated chronic lymphocytic leukaemia (CLL).

Follicular lymphoma.

Gazyva in combination with chemotherapy followed by Gazyva maintenance is indicated for the treatment of patients with previously untreated advanced follicular lymphoma.
Gazyva in combination with bendamustine, followed by Gazyva maintenance, is indicated for the treatment of patients with follicular lymphoma (FL) who did not respond to, or who progressed during or up to 6 months after treatment with rituximab or a rituximab containing regimen.

Pre-treatment to reduce the risk of cytokine release syndrome (CRS) induced by glofitamab.

Gazyva is indicated as a pre-treatment to reduce the risk of cytokine release syndrome (CRS) induced by glofitamab.

4.2 Dose and Method of Administration

Dose.

Substitution by any other biological medicinal product requires the consent of the prescribing physician.

General.

Gazyva should be administered as an intravenous infusion through a dedicated line in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced physician. Gazyva infusions should not be administered as an intravenous push or bolus. Isotonic 0.9% sodium chloride solution should be used as the infusion vehicle (see Section 6.6 Special Precautions for Disposal).

Prophylaxis and premedication for tumour lysis syndrome (TLS).

Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidase (e.g. rasburicase), prior to start of Gazyva infusion as per standard practice (see Section 4.4 Special Warnings and Precautions for Use). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.

Prophylaxis and premedication for infusion related reactions (IRR).

Premedication to reduce the risk of IRRs (see Section 4.4 Special Warnings and Precautions for Use) is outlined in Table 1. Corticosteroid premedication is recommended for FL patients and mandatory for CLL patients for the first infusion and patients receiving Gazyva as a pre-treatment. Premedication for subsequent infusions and other premedication should be administered as described below. Patients with a high tumour burden and/or (i.e. high peripheral circulating lymphocyte count in CLL (> 25 x 109/L)) may be at increased risk of severe IRR.
Hypotension as a symptom of IRR may occur during Gazyva intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion, and for the first hour after administration (see Section 4.4 Special Warnings and Precautions for Use).

Standard dosage.

Chronic lymphocytic leukaemia (in combination with chlorambucil*).

Cycle 1.

The recommended dosage of Gazyva is 1000 mg administered over day 1 and 2, and on day 8 and day 15 of the first 28 day treatment cycle as shown in Table 2.
Two infusion bags should be prepared; one for the first infusion of 100 mg and one for the second infusion of 900 mg. If the 100 mg dose is completed without modifications of the infusion rate or interruptions, the 900 mg dose can be administered on the same day (no dose delay necessary) provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the 900 mg infusion must be administered the following day (see Table 2).

Cycles 2-6.

The recommended dosage of Gazyva is 1000 mg administered on day 1 for each 28 day treatment cycle as shown in Table 2.

Delayed or missed doses (CLL).

If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyva should be maintained between doses thereafter.
Follicular lymphoma. The recommended dosage of Gazyva is 1000 mg administered intravenously according to Table 3.

Previous untreated follicular lymphoma.

For patients with previously untreated follicular lymphoma, Gazyva should be administered with chemotherapy as follows:
six 28 day cycles in combination with bendamustine** or;
six 21 day cycles in combination with CHOP, followed by 2 additional cycles of Gazyva alone or;
eight 21 day cycles in combination with CVP.
Previously untreated patients who achieve a complete or partial response to Gazyva plus chemotherapy should continue to receive Gazyva (1000 mg) alone as maintenance therapy once every 2 months until disease progression or for up to 2 years.

Relapsed/refractory follicular lymphoma.

For patients with follicular lymphoma who have relapsed after or who are refractory to rituximab or a rituximab-containing regimen, Gazyva should be administered in six 28-day cycles in combination with bendamustine**.
Relapsed/refractory patients who achieve complete or partial response or have stable disease should continue to receive Gazyva 1000 mg alone as maintenance therapy once every 2 months until disease progression or for up to 2 years.
Gazyva should be administered at the standard infusion rate in Cycle 1 (see Table 3). In patients who do not experience Grade ≥ 3 infusion related reactions (IRRs) during Cycle 1, Gazyva may be administered as a short (approximately 90 minutes) duration infusion (SDI) from Cycle 2 onwards (see Table 4).

Delayed or missed doses (FL).

If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose.
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15 requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.
During maintenance, maintain the original dosing schedule for subsequent doses.
Pre-treatment to reduce the risk of CRS induced by glofitamab. The recommended dose for pre-treatment is a single 1000 mg dose of Gazyva administered intravenously, 7 days prior to initiation of glofitamab. Refer to the glofitamab Product Information for more information.
Administer Gazyva at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Dosage modifications during treatment (all indications).

No dose reductions of Gazyva are recommended.
For management of symptomatic adverse events (including IRRs), see Table 5; see Section 4.4 Special Warnings and Precautions for Use.
Special populations.

Children.

The safety and efficacy of Gazyva in children below 18 years of age have not been established.

Elderly.

No dose adjustment is required in elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No dose adjustment is required in patients with mild or moderate renal impairment. Gazyva has not been studied in patients with a CrCl < 30 mL/min (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

The safety and efficacy of Gazyva in patients with hepatic impairment have not been established.

Method of administration.

Instructions for dilution. Gazyva should be prepared by a healthcare professional using aseptic technique. Use a sterile needle and syringe to prepare Gazyva.

For CLL cycles 2-6, all FL cycles and as a pre-treatment to reduce the risk of CRS induced by glofitamab.

Withdraw the required amount of Gazyva liquid concentrate from the vial and dilute in a PVC or non-PVC polyolefin infusion bag containing the appropriate volume of sterile, non-pyrogenic 0.9% aqueous sodium chloride solution. Do not use dextrose containing solutions or other diluents (see Section 6.2 Incompatibilities).

For CLL cycle 1, day 1 only: preparation of infusion bags for dose administered over 2 days.

Table 6 provides guidance on the volume of Gazyva liquid concentrate to be diluted and the volume of sterile 0.9% sodium chloride solution it is to be diluted in. Withdraw the required amount of Gazyva liquid concentrate from the vial and dilute in a PVC or non-PVC polyolefin infusion bag containing the appropriate volume of sterile, non-pyrogenic 0.9% aqueous sodium chloride solution. Do not use dextrose-containing solutions or other diluents (see Section 6.2 Incompatibilities).
To ensure differentiation of the two infusion bags for the initial 1000 mg dose, the recommendation is to utilise bags of different sizes to distinguish between the 100 mg dose for cycle 1 day 1 and the 900 mg dose for cycle 1 day 1 (continued) or day 2. To prepare the 2 infusion bags, withdraw 40 mL of Gazyva liquid concentrate from the vial and dilute 4 mL into a 100 mL infusion bag and the remaining 36 mL into a 250 mL PVC or non-PVC polyolefin infusion bag containing sterile, non-pyrogenic 0.9% aqueous sodium chloride solution. Clearly label each infusion bag.
Each bag should be gently inverted to mix the solution in order to avoid foaming.
Parenteral drug products should be inspected visually for particulates and discolouration prior to administration.
Gazyva is for single use in one patient only. Once the infusion is prepared it should be administered immediately (see Section 6.4 Special Precautions for Storage).

4.3 Contraindications

Gazyva is contraindicated in patients with a known hypersensitivity to obinutuzumab, murine proteins or to any of the excipients.

4.4 Special Warnings and Precautions for Use

In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded in the patient medical record.
In study BO21223 of patients with previously untreated follicular lymphoma (FL), Gazyva plus chemotherapy compared with rituximab plus chemotherapy demonstrated a higher incidence of adverse events (AEs), in particular serious AEs, Grade 3-5 AEs and infections. Prescribers should consider this when choosing to prescribe Gazyva for patients with previously untreated FL, particularly for patients who are older age (65 years and over), or have reduced renal function.

Infusion related reactions (IRRs).

The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyva were infusion related reactions (IRRs) which occurred predominantly during infusion of the first 1000 mg.
In CLL patients who received the combined measures for prevention of IRRs (corticosteroid; oral analgesic/ anti-histamine (H1 histamine receptor blockade); omission of antihypertensive medication in the morning of the first infusion; cycle 1 day 1 dose administered over 1 or 2 days; see Section 4.2 Dose and Method of Administration) decreased incidence of IRRs of all grades was observed. The incidence of IRRs was independent of the corticosteroid pre-medication given (prednisone/ prednisolone or methylprednisolone/ dexamethasone). The incidence of grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see Section 4.2 Dose and Method of Administration). The incidence and severity of infusion related symptoms decreased substantially after the first 1000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyva (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from IgE mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL (> 25 x 109/L) may be at increased risk of severe IRR. See Section 4.2 Dose and Method of Administration for information on prophylaxis and Table 5 for advice on how to manage IRRs based on Grade of reaction.
Patients should not receive further Gazyva infusions if they experience:
acute life threatening respiratory symptoms;
other life threatening anaphylactoid symptoms;
a grade 4 (i.e. life threatening) IRR; or
a second occurrence of a grade 3 (prolonged/ recurrent) IRR (after resuming the first infusion or during a subsequent infusion).
Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyva intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyva infusion, and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medication.

Hypersensitivity reactions.

Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyva. If a hypersensitivity reaction is suspected during or after an infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion should be stopped, appropriate treatment of the hypersensitivity reaction should be commenced, and Gazyva treatment permanently discontinued. Patients with known hypersensitivity to Gazyva must not be treated (see Section 4.3 Contraindications). Hypersensitivity may be clinically difficult to distinguish from IRRs.
In a 26 week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (Cmax and AUC0-168 h at steady-state (day 176) after weekly administration of 5, 25, and 50 mg/kg, were 377, 1530, and 2920 microgram/mL and 39,800, 183,000, and 344,000 (microgram.h)/mL, respectively). Findings included acute anaphylactic or anaphylactoid reactions and an increased prevalence of systemic inflammation and infiltrates consistent with immune complex mediated hypersensitivity reactions, such as arteritis/ periarteritis, glomerulonephritis, and serosal/ adventitial inflammation. These reactions led to unscheduled termination of 6/36 animals treated with Gazyva during dosing and recovery phases; these changes were partially reversible. No renal toxicity with a causal relationship to Gazyva has been observed in humans.

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) has been reported with Gazyva. Patients who are considered to be at risk of TLS [e.g. patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min)] should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidase (e.g. rasburicase), prior to the infusion of Gazyva as described (see Section 4.2 Dose and Method of Administration). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines should also be followed, according to standard practice. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated (see Section 4.4 Special Warnings and Precautions for Use).

Neutropenia.

Severe and life threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyva. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. Concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered. If treatment is necessary, it should be administered in accordance with local guidelines, and administration of granulocyte colony stimulating factors (G-CSF) should be considered. Late onset neutropenia (occurring 28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/ stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia.

Thrombocytopenia.

Severe and life threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyva. Fatal haemorrhagic events have also been reported in cycle 1 in patients treated with Gazyva. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician.
Use of any concomitant therapies which could possibly worsen thrombocytopenia related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.

Coagulation abnormalities including disseminated intravascular coagulation (DIC).

Disseminated intravascular coagulation (DIC) has been reported in patients receiving obinutuzumab for treatment of follicular lymphoma and chronic lymphocytic leukaemia. In the majority of cases, the events have involved subclinical (asymptomatic) changes in platelets and laboratory coagulation parameters following the first infusion, with spontaneous resolution usually occurring within one to two weeks. In some cases, the events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC have been identified (see Section 4.8 Adverse Effects (Undesirable Effects)).

Worsening of pre-existing cardiac conditions.

In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyva (see Section 4.8 Adverse Effects (Undesirable Effects)). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.

Infections.

Gazyva should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyva in patients with a history of recurring or chronic infections. Serious, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyva therapy. Fatal infections have been reported. Patients with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections.
In the FL studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in maintenance. During the follow-up phase, Grade 3-5 infections are observed more in patients who received Gazyva plus bendamustine in the induction phase.

Hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyva (see Section 4.8 Adverse Effects (Undesirable Effects)). HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e. HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).
Screen all patients for HBV infection by measuring HBsAg and anti-HBc. The results of HBsAg and anti-HBc testing should be known in all patients before initiating treatment with Gazyva. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for at least 12 months following treatment with Gazyva. HBV reactivation has been reported for other CD20 directed cytolytic antibodies following completion of therapy.
In patients who develop reactivation of HBV while receiving Gazyva, immediately discontinue Gazyva and any concomitant chemotherapy, and institute appropriate treatment and refer the patient to a gastroenterologist. Resumption of Gazyva in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming Gazyva in patients who developed HBV reactivation.

Progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyva (see Boxed Warnings; see Section 4.8 Adverse Effects (Undesirable Effects)). The diagnosis of PML should be considered in any patient presenting with new onset or changes to pre-existing neurologic manifestations. The symptoms of PML are non-specific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/ symptoms regarded as "cortical" (e.g. aphasia or visual spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (CSF testing for JC viral DNA). Therapy with Gazyva should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.

Immunisation.

The safety of immunisation with live or attenuated viral vaccines, during or following Gazyva therapy has not been studied. Vaccination with live virus vaccines is not recommended during treatment and until B cell recovery. Treatment with Gazyva following vaccination should only commence once protective antibody titres have been reached.

Exposure in utero to Gazyva and vaccination of infants with live virus vaccines.

Due to the potential depletion of B cells in infants of mothers who have been exposed to Gazyva during pregnancy, the safety and timing of vaccinations with live virus vaccines should be discussed with the child's healthcare provider. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyva during pregnancy until the infants' B cell levels are within normal ranges (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in renal impairment.

Chronic lymphocytic leukaemia.

In the pivotal study in CLL, 27% (90 out of 336) of patients treated with Gazyva plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than those associated with CrCl ≥ 50 mL/min (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). No significant differences in efficacy were observed between patients with CrCl < 50 mL/min and those with CrCl ≥ 50 mL/min. Patients with CrCl < 30 mL/min were excluded from the study (see Section 5.1 Pharmacodynamic Properties).

Non-Hodgkin lymphoma (NHL).

In the pivotal studies in iNHL, 6.9% of patients (14 of 204) in study GAO4753g and 5% of patients (35 of 698) in study BO21223 had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events, grade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in Study BO21223 only) than those associated with CrCl ≥ 50 mL/min (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Patients with CrCl < 40 mL/min were excluded from the studies (see Section 5.1 Pharmacodynamic Properties).

Use in hepatic impairment.

The safety and efficacy of Gazyva in patients with hepatic impairment have not been established.

Paediatric use.

The safety and efficacy of Gazyva in children below 18 years of age have not been established.

Use in the elderly.

Chronic lymphocytic leukaemia.

In the pivotal study in CLL, 46% (156 out of 336) of patients treated with Gazyva plus chlorambucil were 75 years old or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than patients < 75 years of age. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age (see Section 5.1 Pharmacodynamic Properties).

Non-Hodgkin lymphoma.

In the pivotal studies in iNHL, patients ≥ 65 years of age experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age. No clinically meaningful differences in efficacy were observed. Table 7 outlines treatment-related AEs by age group for patients enrolled in study BO21223.

Effect on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug-drug interaction studies have been performed, although limited drug interaction sub-studies have been undertaken for Gazyva with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC (fludarabine, cyclophosphamide) and chlorambucil. Co-administration with Gazyva had no effect on the pharmacokinetics of bendamustine, FC or the individual components of CHOP; in addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyva. A risk for interactions with concomitantly used medicinal products cannot be excluded.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific studies in animals have been performed to evaluate the effect of Gazyva on fertility. No adverse effects on male and female reproductive organs were observed in repeat dose toxicity studies in cynomolgus monkeys at up to 100 mg/kg/day for 3 months (8 times the clinical exposure based on AUC at the clinical dose of 1000 mg/kg, 3 doses per 28 day cycle) and 50 mg/kg/day for 6 months (6 times the clinical exposure based on AUC).
(Category C)
Gazyva should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. Women of child-bearing potential should use effective contraception while receiving Gazyva and for 18 months following treatment with Gazyva (see Section 5.2 Pharmacokinetic Properties). Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyva during pregnancy until the infants' B cell levels are within normal ranges.
No studies in pregnant women have been performed. A reproduction study in pregnant cynomolgus monkeys showed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitum day 20 to delivery resulted in complete depletion of B lymphocytes, opportunistic infections and immune complex mediated hypersensitivity reactions in infants at weekly intravenous obinutuzumab doses of 25 and 50 mg/kg (2-5 times the clinical exposure based on Cmax and AUC). Offspring exposures on day 28 postpartum (mean Cmax 80-240 microgram/mL, in the range of concentrations in maternal serum) and very low concentrations in milk (less than 0.5% of the corresponding maternal serum levels) suggest in utero exposure. B cell counts returned to normal levels in the infants, and immunologic function was restored within 6 months of birth. Furthermore, the serum concentrations of Gazyva in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that Gazyva crosses the placenta.
 As human IgG is secreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during Gazyva therapy and for 18 months after the last dose of Gazyva (see Section 5.2 Pharmacokinetic Properties). Animal studies have shown excretion of Gazyva in breast milk (see Section 4.6 Fertility, Pregnancy and Lactation).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Gazyva on the ability to drive and to use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.

4.8 Adverse Effects (Undesirable Effects)

Chronic lymphocytic leukaemia.

The adverse drug reactions (ADRs) described in this section were identified during treatment and follow-up from the pivotal clinical trial, BO21004/CLL11, in which Gazyva was given in combination with chlorambucil compared to chlorambucil alone (stage 1) or rituximab plus chlorambucil (stage 2). In patients treated with Gazyva in combination with chlorambucil, 81% received all 6 treatment cycles compared to 89% of patients in the rituximab plus chlorambucil arm and 67% of patients in the chlorambucil alone arm.
Tables 8 and 9 summarise the ADRs that occurred at a higher incidence (difference of ≥ 2%) in patients receiving Gazyva plus chlorambucil as compared to chlorambucil alone or rituximab plus chlorambucil, respectively.

Non-Hodgkin lymphoma.

In patients with FL, the profile of adverse drug reactions (ADRs) was consistent with the overall iNHL population.
ADRs described in this section were identified during induction, maintenance and follow-up in 2 pivotal studies that investigated Gazyva in combination with bendamustine, CHOP, or CVP followed by Gazyva maintenance therapy in:
Patients with previously untreated iNHL (study BO21223, n=1390; 692 patients in the rituximab plus chemotherapy arm, and 698 patients in the Gazyva plus chemotherapy arm), of whom 86% had FL. Of these patients, 92.7% who were treated with Gazyva plus chemotherapy (induction) received all 6 or 8 treatment cycles (depending on the chemotherapy) of Gazyva.
Patients with relapsed/refractory iNHL (study GAO4753g, n=407; 203 patients in the bendamustine arm, and 204 in the Gazyva plus bendamustine arm), of whom 81% had FL. Of these patients, 79.4% who were treated with Gazyva plus bendamustine received all 6 treatment cycles of Gazyva.
The adverse drug reactions (ADRs) described in Table 10 this section (based on a safety population of 407 patients with indolent NHL) were identified during induction, maintenance, and follow-up from study GAO4753g, in which Gazyva was given in combination with bendamustine during induction (G+B), and as Gazyva monotherapy in maintenance and compared to bendamustine during induction alone (B). In patients treated with G+B, 79.4% received all 6 treatment cycles of Gazyva and 75.6% received all 6 cycles of B compared to 66.7% of patients in the B arm.
Table 10 summarises the ADRs that occurred at a higher incidence (difference of ≥ 2%) in patients receiving G+B during induction followed by Gazyva maintenance as compared to B during induction alone.
In study GAO4753g, patients in the B arm received 6 months of induction treatment only, whereas after the induction period, patients in the G+B arm continued on with Gazyva maintenance treatment. During the maintenance period with Gazyva, the most common adverse reactions were cough (20.3%), neutropenia (12.7%), upper respiratory tract infections (12.0%), diarrhoea (10.1%), bronchitis (9.5%), sinusitis (9.5%), nausea (8.9%), fatigue (8.9%), IRRs (8.2%), urinary tract infections (7.0%), nasopharyngitis (7.0%), pyrexia (7.0%), arthralgia (6.3%), vomiting (5.7%), rash (5.7%), pneumonia (5.1%), dyspnoea (5.1%) and pain in extremity (5.1%). The most common grade 3-5 adverse reactions were neutropenia (10.8%), febrile neutropenia (1.9%) and anaemia, thrombocytopenia, pneumonia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1.3%).
The adverse drug reactions (ADRs) described in Table 11 (based on a safety population of 1390 patients with indolent NHL) were identified during induction, maintenance and follow-up from study BO21223, in which patients were treated with either Gazyva or rituximab in combination with chemotherapy followed by Gazyva or rituximab monotherapy in responding patients, every 2 months until disease progression or for a maximum of 2 years. During combination therapy with chemotherapy, 93% of patients received all treatment cycles of Gazyva and 92% of patients received all treatment cycles of rituximab. Of the responding patients who commenced monotherapy with Gazyva or rituximab, 77% and 73% completed the full course, respectively.
Table 11 summarises the ADRs that occurred at a higher incidence (difference of ≥ 2%) in patients receiving Gazyva plus chemotherapy during induction followed by Gazyva maintenance as compared to rituximab plus chemotherapy during induction followed by rituximab maintenance in study BO21223.
During the monotherapy period with Gazyva, the most common adverse events (incidence ≥ 5%) in patients with previously untreated iNHL were cough (20%), neutropenia (19%), upper respiratory tract infection (14%), viral upper respiratory tract infection (15%), diarrhoea (12%), arthralgia (9%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (6%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%) and vomiting (5%). The most common Grade 3-4 adverse events (incidence ≥ 1%) during the monotherapy period were neutropenia (17%), pneumonia (3%, with 2 deaths due to pneumonia reported in the Gazyva treatment arm) and febrile neutropenia (2%).

Further information on selected adverse reactions.

Infusion related reactions. Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see Section 4.4 Special Warnings and Precautions for Use).
In study BO21223 the most frequent symptoms of IRRs (> 5% occurrence in the G-chemo arm) were as follows (percentages expressed as R-chemo vs. G-chemo): nausea (20.3% vs. 25.7%), chills (7.0% vs. 15.6%), pyrexia (5.5% vs. 14.3%), chest discomfort (3.4% vs. 5.0%), vomiting (8.0% vs. 11.1%), fatigue (6.9% vs. 7.2%), dyspnoea (4.7% vs. 7.6%), throat irritation (5.4% vs. 3.5%), headache (4.4% vs. 8.7%), flushing (3.7% vs. 5.4%), hypotension (1.7% vs. 5.0%), pruritus (6.0% vs. 4.0%), rash (5.9% vs. 4.2%) and constipation (3.0% vs. 5.4%).

Chronic lymphocytic leukaemia.

The incidence of IRRs was 65% with the infusion of the first 1000 mg of Gazyva (20% of patients experiencing a grade 3-4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyva. The incidence of IRR with subsequent infusions was 3% with the second 1000 mg dose and 1% thereafter. No grade 3-5 IRR were reported beyond the first 1000 mg infusions of cycle 1.
In patients who received the recommended measures for prevention of IRRs as described (see Section 4.2 Dose and Method of Administration), a decreased incidence of all grades IRRs was observed. The incidence of grade 3-4 IRRs (which are based on a relatively low number of patients) were similar before and after mitigation measures were implemented.

Non-Hodgkin lymphoma.

In cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyva plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyva plus chemotherapy, the incidence of IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyva.
Overall, 3% of patients experienced an IRR leading to discontinuation of Gazyva.

Short duration infusion in patients with follicular lymphoma.

Study MO40597/GAZELLE was designed to characterise the safety profile of short duration Gazyva infusions (approximately 90 minutes) from Cycle 2 in patients with previously untreated FL.
In study MO40597 a greater proportion of patients experienced any grade IRRs at Cycle 2 compared to the proportion who experienced IRRs after standard infusion at Cycle 2 in study BO21223 (10/99 [10.1%] vs. 23/529 [4.3%] respectively; IRRs attributed by the investigator to any component of study therapy). No patients experienced Grade ≥ 3 IRRs after SDI at Cycle 2 in study MO40597; 3/529 (0.6%) experienced Grade ≥ 3 IRRs at Cycle 2 in study BO21223. IRR symptoms and signs were similar in both studies. Infusion related reactions observed in study MO40597/GAZELLE are summarised in Table 12.
Neutropenia and infections.

Chronic lymphocytic leukaemia.

The incidence of neutropenia was higher in the Gazyva plus chlorambucil arm compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte colony stimulating factors. The incidence of infection was 38% in the Gazyva plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with grade 3-5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyva plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyva plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see Section 4.4 Special Warnings and Precautions for Use).

Non-Hodgkin lymphoma.

In the Gazyva plus chemotherapy arm, the incidence of neutropenia was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia in the Gazyva plus chemotherapy arm were 3% and 7%, respectively. The incidence of infection was 81% in the Gazyva plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 2% of patients). The incidence of infection was 72% in the rituximab plus chemotherapy arm (with Grade 3-5 events reported in 17% of patients and fatal events reported in 1% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see Section 4.4 Special Warnings and Precautions for Use).

Short duration infusion in patients with follicular lymphoma.

In study MO40597, assessing the safety of SDI, neutropenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients received standard duration infusion (69/113 [61.1%] vs. 247/595 [41.5%] respectively, throughout induction). The median and range of neutrophil count values were similar in both studies at each time point. Febrile neutropenia was reported in a similar proportion of patients in study MO40597 and study BO21223 (6/113 [5.3%] vs. 31/595 [5.2%] respectively). Infection was reported less frequently in study MO40597 than in study BO21223 (45/113 [39.8%] vs. 284/595 [47.7%] respectively).
Thrombocytopenia and haemorrhagic events.

Chronic lymphocytic leukaemia.

The incidence of thrombocytopenia was higher in the Gazyva plus chlorambucil arm compared to the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated with Gazyva plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyva infusion) (see Section 4.4 Special Warnings and Precautions for Use). The overall incidence of haemorrhagic events was similar in the Gazyva treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however all of the events in patients treated with Gazyva were reported in cycle 1. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Non-Hodgkin lymphoma.

Thrombocytopenia occurred more frequently during Cycle 1 in the Gazyva plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients treated with Gazyva plus chemotherapy than in the relevant comparator arm. The incidence of haemorrhagic AEs was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 4% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients, none of these fatal AEs occurred in Cycle 1.

Short duration infusion in patients with follicular lymphoma.

In study MO40597, assessing the safety of SDI, thrombocytopenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients received standard duration infusion (21/113 [18.6%] vs. 63/595 [10.6%] respectively, throughout induction). The median and range of platelet count values were similar in both studies at each time point. No thrombocytopenia events reported in study MO40597 were associated with bleeding.

Coagulation abnormalities including disseminated intravascular coagulation (DIC).

DIC has been reported in patients receiving obinutuzumab for treatment of follicular lymphoma and chronic lymphocytic leukemia. In some cases, the events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC have been identified. Three patients were reported with DIC (one serious, two non-serious) among a total of 1837 obinutuzumab-treated patients in four major company-sponsored controlled trials in Non-Hodgkin's Lymphoma. All events occurred in the obinutuzumab treatment groups; no cases were reported in the comparator groups. All events occurred within 1-2 days after the first infusion. All patients continued treatment (see Section 4.4 Special Warnings and Precautions for Use).
Progressive multifocal leukoencephalopathy (PML). PML has been reported in patients treated with Gazyva (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use).
Hepatitis B reactivation. Cases of hepatitis B reactivation have been reported in patients treated with Gazyva (see Section 4.4 Special Warnings and Precautions for Use).
Worsening of pre-existing cardiac conditions. Cases of fatal cardiac events have been reported in patients treated with Gazyva (see Section 4.4 Special Warnings and Precautions for Use).
Gastrointestinal perforation. Cases of gastro-intestinal perforation have been reported in patients receiving Gazyva, mainly in NHL.
Malignancies. There is an increased incidence of second malignancies in patients with CLL. Data from the pivotal study in CLL does not demonstrate an increased risk of second malignancies following Gazyva therapy.

Laboratory abnormalities.

Transient elevation in liver enzymes (AST, ALT, ALP) has been observed shortly after the first infusion of Gazyva.
For additional information see Section 4.8 Adverse Effects (Undesirable Effects).

Reporting of suspected adverse reactions.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

No experience with overdosage is available from human clinical trials. In clinical trials with Gazyva, doses ranging from 50 mg up to and including 2000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose dependent. Patients who experience overdose should have immediate interruption or reduction of their infusion and should be closely supervised. Patients should be closely monitored with regular blood cell counts, and for increased risk of infections, while B cell-depleted.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01FA03.

Mechanism of action.

Obinutuzumab specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B lymphocytes. CD20 is not expressed on haemopoietic stem cells, pro-B cells, or normal plasma cells. Glycoengineering of the Fc part of obinutuzumab results in higher affinity for FcγRIII receptors on immune effector cells such as natural killer (NK) cells and macrophages and monocytes as compared to non-glycoengineered antibodies.
In nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) through recruitment of FcγRIII positive immune effector cells. In addition, obinutuzumab mediates a low degree of complement dependent cytotoxicity (CDC). In animal models, obinutuzumab mediates potent B cell depletion and anti-tumour efficacy. Compared to type I CD20 antibodies, obinutuzumab, a type II antibody, is characterised by a direct cell death induction with a concomitant reduction in CDC. Compared to non-glycoengineered CD20 antibodies, obinutuzumab is characterised by greater ADCC and phagocytosis (ADCP) as a consequence of the glycoengineering, but in vivo studies in xenograft tumour models in SCID mice showed no difference in tumour growth inhibition between obinutuzumab and non-glycoengineered wild type obinutuzumab.
Pre-treatment with obinutuzumab to deplete peripheral blood and lymphoid tissue B cells was shown to attenuate glofitamab-induced cytokine release and related adverse effects in cynomolgus monkeys and tumour-bearing humanised mice.
In the pivotal clinical trial in patients with CLL BO21004/CLL11, 91% (40 out of 44) of evaluable patients treated with Gazyva were B cell depleted (defined as CD19+ B-cell counts < 0.07 x 109/L) at the end of treatment period and remained depleted during the first 6 months of follow-up. Recovery of B cells was observed within 12 to 18 months of follow-up in 35% (14 out of 40) of patients without progressive disease and 13% (5 out of 40) with progressive disease.

Clinical trials.

Chronic lymphocytic leukaemia (CLL).

A phase III, international, multicentre, open-label, randomised, two-stage, three arm study (BO21004/CLL11) investigating the safety and efficacy profile of Gazyva plus chlorambucil compared to rituximab plus chlorambucil or chlorambucil alone was conducted in patients with previously untreated CLL with comorbidities.
Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the following measures of coexisting medical conditions: comorbidity score [total Cumulative Illness Rating Scale (CIRS)] of greater than 6 or reduced renal function as measured by CrCl < 70 mL/min. Patients with inadequate liver function (NCICTC grade 3 liver function tests (AST, ALT > 5 x ULN for > 2 weeks; bilirubin > 3 x ULN)) and renal function (CrCl < 30 mL/min) were excluded.
A total of 781 patients were randomised 2:2:1 to receive Gazyva plus chlorambucil, rituximab plus chlorambucil or chlorambucil alone. Stage 1 compared Gazyva plus chlorambucil to chlorambucil alone in 356 patients and stage 2 compared Gazyva plus chlorambucil to rituximab plus chlorambucil in 663 patients. Efficacy results are summarised in Table 13 and in Figures 1-3.
In the majority of patients, Gazyva was given intravenously as a 1000 mg initial dose administered on day 1, day 8 and day 15 of the first treatment cycle. In order to reduce the rate of infusion related reactions in patients, an amendment was implemented and 140 patients received the first Gazyva dose administered over 2 days (day 1 (100 mg) and day 2 (900 mg), see Section 4.2 Dose and Method of Administration). For each subsequent treatment cycle (cycles 2 to 6), patients received Gazyva 1000 mg on day 1 only. Chlorambucil was given orally at 0.5 mg/kg bodyweight on day 1 and day 15 of all treatment cycles (1 to 6).
The demographics data and baseline characteristics were well balanced between the treatment groups. The majority of patients enrolled were Caucasian (95%) and male (61%). The median age was 73 years, with 44% being 75 years or older. At baseline, 22% of patients had Binet stage A, 42% had Binet stage B and 36% had Binet stage C. The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity score above 6. The median estimated CrCl was 62 mL/min and 66% of all patients had a CrCl < 70 mL/min. Forty-two percent of patients enrolled had both a CrCl < 70 mL/min and a comorbidity score of > 6. Thirty-four percent of patients were enrolled on comorbidity score alone, and 23% of patients were enrolled with only impaired renal function.
The most frequently reported coexisting medical conditions (using a cut off of 30% or higher) in the MedDRA body systems are: vascular disorders 73%, cardiac disorders 46%, gastrointestinal disorders 38%, metabolism and nutrition disorders 40%, renal and urinary disorders 38%, musculoskeletal and connective tissue disorders 33%.
The primary endpoint of the study was investigator assessed progression free survival (PFS-INV). In addition, an independent review committee (IRC) assessed all patients for progression and IRC assessed PFS (PFS-IRC) was evaluated.
Key secondary efficacy endpoints were end of treatment response, molecular remission at end of treatment (minimal residual disease status) and time to event endpoints (event free survival, new anti-leukaemic therapy). Overall survival for stage 1 is presented in Figure 2. Overall survival for stage 2 will continue to be followed and is not yet mature.
Results of the PFS subgroup analysis (i.e. sex, age, Binet stages, CrCl, CIRS score, beta2-microglobulin, IGVH status, chromosomal abnormalities, lymphocyte count at baseline) were consistent with the results seen in the overall ITT population. The risk of disease progression or death was reduced in the Gazyva plus chlorambucil (GClb) arm compared to the rituximab plus chlorambucil (RClb) arm and the chlorambucil (Clb) alone arm in all subgroups. The hazard ratios ranged from 0.08 to 0.42 for GClb vs Clb and 0.28 to 0.71 for GClb vs RClb.

Patient reported outcomes.

In the QLQC30 and QLQ-CLL-16 questionnaires conducted during the treatment period, no substantial difference in any of the subscales was observed. Data during follow-up, especially for the chlorambucil alone arm, is limited. However, no notable differences in quality of life during follow-up have been identified to date.
Health-related quality of life assessments, specific to fatigue through treatment period, show no statistically significant difference suggesting that the addition of Gazyva to chlorambucil regimen does not increase the experience of fatigue for patients. See Figures 1 to 3.

Non-Hodgkin lymphoma (follicular lymphoma).

Previously untreated follicular lymphoma. In a multicentre phase III, open-label, randomised study (BO21223/GALLIUM), 1401 previously untreated patients with either stage II (bulky)/III/IV follicular lymphoma (FL) (n=1202) or marginal zone lymphoma (MZL) (n=199) were randomised. Of the 199 patients randomised to the MZL cohort, 4 presented with a non-MZL histology. Patients were randomised 1:1 to receive either Gazyva or rituximab in combination with chemotherapy (CHOP, CVP, or bendamustine) followed by Gazyva or rituximab maintenance in patients who achieved a complete or partial response. The remainder of the study description focuses on the FL population.
The demographic data and baseline characteristics of the FL population were well balanced. The median age was 59 years, the majority of patients were Caucasian (81%), and female (53%). Seventy-nine percent of patients had a FLIPI score of ≥ 2. Seven percent had Stage II (bulky) disease, 35% had Stage III disease and 57% had Stage IV disease. Fifty-seven percent received bendamustine, 33% received CHOP, and 10% received CVP chemotherapy. Forty-four percent had bulky disease (> 7 cm), 34% had at least one B-symptom at baseline and 97% had an ECOG performance status of 0-1 at baseline.
Gazyva (1000 mg) was administered intravenously prior to chemotherapy as described (see Section 4.2 Dose and Method of Administration, Follicular lymphoma). Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyva. Standard dosing of CHOP (n=6 cycles) and CVP (n=8 cycles) was given. Following Cycles 6-8, when Gazyva was given in combination with chemotherapy, Gazyva maintenance therapy was given every 2 months for 2 years for responding patients or until disease progression.
Efficacy results are summarised in Table 14. Kaplan-Meier curves for PFS are shown in Figure 4.
Response rates at the end of induction assessed by positron emission tomography (PET) were available for 297 of 601 patients in the Gazyva plus chemotherapy arm and 298 of 601 patients in the rituximab plus chemotherapy arm of the study. Complete response rates at end of induction as assessed by PET were 62.3% in the Gazyva plus chemotherapy arm and 56.7% in the rituximab plus chemotherapy arm. Overall response rates were similar in the two arms, with a difference of 4.3% in favour of the Gazyva plus chemotherapy arm (85.9% for G-chemo vs 81.5% for R-chemo). The differences were 4.3% (OR, 95% CI [-1.8, 10.4], p=0.19) and 5.6% (CR, 95% CI [-2.5, 13.6], p=0.28).

Results of subgroup analyses.

Results of subgroup analyses were, in general, consistent with the results seen in the FL population, supporting the robustness of the overall result. The subgroups evaluated included IPI, FLIPI, Chemo Regimen, Bulky Disease, B Symptoms at Baseline, Ann Arbor Stage and ECOG at Baseline.
Relapsed/refractory follicular lymphoma. In a phase III, open label, multicentre, randomised study (GAO4753g/GADOLIN), 396 patients with indolent NHL (iNHL), who had no response or who progressed during or up to 6 months after treatment, with rituximab or a rituximab-containing regimen, were evaluated. Patients were randomised 1:1 to receive either bendamustine (B) alone (n = 202) or Gazyva in combination with bendamustine (G+B) (n = 194) for 6 cycles, each of 28 days duration. Patients in the G+B arm who did not have disease progression [i.e. patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of induction continued receiving Gazyva maintenance until disease progression or for up to two years (whichever occurred first).
The demographic data and baseline characteristics were well balanced [median age was 63 years; the majority of patients were Caucasian (88%) and male (58%)]. The median time from initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10); 44% of patients had received 1 prior therapy and 34% of patients had received 2 prior therapies. The majority of the patients had follicular lymphoma (FL) (81.1%). Of the non-follicular patients, 11.6% had marginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL).
Gazyva was given intravenously as a 1000 mg dose on days 1, 8 and 15 of cycle 1, on day 1 of cycles 2-6, and in patients who did not have disease progression, every 2 months for up to 2 years or until disease progression. Bendamustine was given intravenously on days 1 and 2 for all treatment cycles (cycles 1-6) at 90 mg/m2/day when given in combination with Gazyva or 120 mg/m2/day when given alone.
The primary analysis demonstrated a statistically significant and clinically meaningful 52% reduction in the risk of disease progression (PD) or death, based on IRC assessment, in patients with FL receiving G+B followed by G maintenance vs B alone (stratified log-rank test p-value ≤ 0.0001). IRC-assessed response rates at the end of induction treatment and IRC-assessed best overall response within 12 months of start of treatment were similar in the two treatment arms.
The majority of the patients in study GAO4753g had FL (81.1%). Efficacy results from the primary analysis in the FL population are shown in Table 15 and Figures 5 and 6. 11.6% of the patients had marginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL). In the non-FL population, the HR for IRC-assessed PFS was 0.94 [95% CI: 0.49, 1.90]. No definitive conclusions could be drawn on efficacy in the MZL and SLL sub-populations.
At final analysis, the median observation time was 45.9 months (range: 0-100.9 months) for FL patients in the B arm and 57.3 months (range: 0.4-97.6 months) for patients in the G+B arm, representing an additional 25.6 months and 35.2 months of median follow-up in B and G+B arms, respectively, since the primary analysis. Only Investigator (INV) assessed endpoints were reported at final analysis since IRC assessments did not continue. Overall, the efficacy results were consistent with what was observed in the primary analysis. The overall survival (OS) in patients with FL was stable with longer follow-up (see Figure 6); the HR for risk of death was 0.71 (95% CI: 0.51, 0.98).

Results of subgroup analyses.

Results of subgroup analyses were in general consistent with the results seen in the overall FL population, supporting the robustness of the overall result.
Short duration infusion study (MO40597/GAZELLE). The safety of short (approximately 90 minutes) duration infusion (SDI) of obinutuzumab administered in combination with CHOP, CVP or bendamustine chemotherapy was evaluated in a multicentre, open-label, single arm study in 113 patients with previously untreated advanced follicular lymphoma (Study MO40597/GAZELLE).
Patients received the first cycle of obinutuzumab at the standard infusion rate on Day 1, 8, and 15 of Cycle 1. Patients who did not experience any Grade ≥ 3 IRRs during the first cycle received SDI from Cycle 2 onwards.
The primary endpoint of the study was the proportion of patients who experienced a Grade ≥ 3 IRR associated with SDI during Cycle 2, among those who had previously received 3 administrations of obinutuzumab at the standard infusion rate during Cycle 1 without experiencing a Grade ≥ 3 IRR.
No Grade ≥ 3 IRRs were observed among patients receiving SDI at Cycle 2. After Cycle 2 only one patient experienced a Grade 3 IRR (hypertension at Cycle 5). See Section 4.8 Adverse Effects (Undesirable Effects).
Patient reported outcomes.

Previously untreated follicular lymphoma.

Based on the FACT-Lym questionnaire collected during treatment and follow-up periods, both arms experienced clinically meaningful improvements in lymphoma-related symptoms as defined by a ≥ 3 point increase from baseline in the Lymphoma subscale, a ≥ 6 point increase from baseline in the FACT Lym TOI and a ≥ 7 point increase from baseline in the FACT Lym Total score. EQ-5D utility scores were similar at baseline, during treatment and follow-up. No meaningful differences were seen between the arms in health-related quality of life (HRQoL) or health status measures.

Relapsed/refractory follicular lymphoma.

Based on the FACT-Lym questionnaire and EQ-5D index scale collected during the treatment and follow-up periods, HRQoL was generally maintained in the pivotal study with no meaningful difference between the arms. However, the addition of Gazyva to bendamustine delayed the time to worsening of quality of life as measured by the FACT-Lym TOI score (HR=0.83; 95% CI: 0.60, 1.13).

Pre-treatment to reduce the risk of CRS induced by glofitamab.

Gazyva was used as a pre-treatment to reduce the risk of CRS induced by glofitamab in study NP30179, a Phase I/II, multicentre, open-label, dose-escalation study designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of glofitamab as a single agent following pre-treatment with a fixed dose of Gazyva. All patients dosed with glofitamab monotherapy received Gazyva by intravenous infusion 1000 mg 7 days prior to the first dose glofitamab. Pre-treatment with obinutuzumab 1000 mg was well tolerated in study NP30179. In the overall safety population (n=424), 67.5% of patients (286/424) had B-cell counts < 70 cells/microL at study entry. Following Gazyva and prior to glofitamab administration, almost all patients had B-cell counts < 70 cells/microL (97.5% [314/322] at Cycle 1, Day 7 [C1D7], 95% [40/42] at C1D8), reflecting the depletion of peripheral B cells with Gazyva. No new safety concerns were identified. Refer to the glofitamab Product Information for more information.

Immunogenicity.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, assay robustness to quantities of Gazyva/antibody in circulation, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Gazyva with the incidence of antibodies to other products may be misleading.
Patients in the pivotal CLL trial, BO21004/CLL11, were tested at multiple time-points for anti-therapeutic antibodies (ATA) to Gazyva. In Gazyva treated patients, 8 out of 140 in the randomised phase and 2 out 6 in the run-in phase tested positive for ATA at 12 months of follow-up. Of these patients, none experienced either anaphylactic or hypersensitivity reactions that were considered related to ATA, nor was clinical response affected.
No post-baseline Human Anti-Human Antibody (HAHA) were observed in patients with iNHL treated in study GAO4753g/GADOLIN. In study BO21223/GALLIUM, 1/565 patient (0.2% of patients with a post-baseline assessment) developed HAHA at induction completion. While the clinical significance of HAHA is not known, a potential correlation between HAHA and clinical course cannot be ruled out.

5.2 Pharmacokinetic Properties

A population pharmacokinetic (PK) model was developed to analyse the PK data in 469 patients with indolent non-Hodgkin lymphoma (iNHL), 342 patients with chronic lymphocytic leukaemia (CLL), and 130 patients with diffuse large B cell lymphoma who received Gazyva in phase I, phase II and phase III studies. From the population PK model, after the cycle 6 day 1 infusion in CLL patients, the Cmax value was 465.7 microgram/mL and AUC(T) value was 8,961 microgram.d/mL. In iNHL patients the estimated median Cmax value was 539.3 microgram/mL and AUC(T) value was 10,956 microgram.d/mL.

Absorption.

Obinutuzumab is administered intravenously. There have been no clinical studies performed with other routes of administration.

Distribution.

Following intravenous administration, the volume of distribution of the central compartment (2.72 L), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid.

Metabolism.

The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared by catabolism.

Excretion.

The clearance of obinutuzumab was approximately 0.11 L/day in CLL patients and 0.08 L/day in iNHL patients with a median elimination t1/2 26.4 days in CLL patients and 36.8 days in iNHL patients.
Obinutuzumab elimination comprises two parallel pathways which describe clearance, a linear clearance pathway and a non-linear clearance pathway which changes as a function of time. During initial treatment, the non-linear time-varying clearance pathway is dominant and is consequently the major clearance pathway. As treatment continues, the impact of this pathway diminishes and the linear clearance pathway predominates. This is indicative of target mediated drug disposition (TMDD), where the initial abundance of CD20 cells causes rapid removal of obinutuzumab from the circulation. However, once the majority of CD20 cells are bound with obinutuzumab, the impact of TMDD on PK is minimised.

Pharmacokinetics in special populations.

In the population PK analyses, gender was found to be a covariate which explains some of the interpatient variability, with an 18% greater steady-state clearance (CLss) and a 19% greater volume of distribution (V) in males. However, results from the population analyses have shown that the differences in exposure between genders are not clinically important (with an estimated median AUC and Cmax in CLL patients of 11,282 microgram.d/mL and 578.9 microgram/mL in females and 8,451 microgram.d/mL and 432.5 microgram/mL in males, respectively at cycle 6, and AUC and Cmax in iNHL patients of 13,172 microgram.d/mL and 635.7 microgram/mL in females and 9,769 microgram.d/mL and 481.3 microgram/mL in males, respectively), indicating that there is no need to dose adjust based on gender.

Elderly patients.

The population pharmacokinetic analysis of obinutuzumab showed that age did not affect the pharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics of obinutuzumab among patients < 65 years (n = 454), patients between 65-75 years (n = 317) and patients > 75 years (n = 190).

Paediatric patients.

No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in children.

Renal impairment.

The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect the pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mild creatinine clearance (CrCl 50 to 89 mL/min, n = 464) or moderate (CrCl 30 to 49 mL/min, n = 106) renal impairment were similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n = 383). PK data in patients with severe renal impairment (CrCl 15-29 mL/min) is limited (n = 8), therefore no dosage recommendations can be made.

Hepatic impairment.

No formal PK study has been conducted and no population PK data was collected in patients with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been performed to establish the mutagenic potential of Gazyva.

Carcinogenicity.

No carcinogenicity studies have been performed to establish the carcinogenic potential of Gazyva.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, histidine hydrochloride monohydrate, trehalose dihydrate and poloxamer 188.

6.2 Incompatibilities

No incompatibilities between Gazyva and polyvinyl chloride, polyethylene, polypropylene or polyolefin bags, polyvinyl chloride, polyurethane, or polyethylene infusion sets, as well as optional inline filters with product contact surfaces of polyethersulfone, a 3 way stopcock infusion aid made from polycarbonate, and catheters made from polyetherurethane have been observed in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyva with 0.9% sodium chloride.
Diluted product should not be shaken or frozen. Do not use other diluents such as dextrose (5%) solution to dilute Gazyva since their use has not been tested.

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.
Gazyva does not contain any anti-microbial preservative; therefore, care must be taken to ensure the sterility of the prepared solution. Product is for single use in one patient only. Discard any residue.

Diluted solution.

Physical and chemical stability of the prepared infusion solution of Gazyva has been demonstrated for 24 hours at 2°C-8°C followed by 24 hours at ambient temperature (≤ 30°C) followed by an infusion taking no longer than 24 hours. To reduce microbiological hazard, the prepared infusion solution should be used immediately. If storage is necessary, hold at 2°C-8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Store vial in a refrigerator at 2°C-8°C. Keep vial in the outer carton in order to protect from light. Do not freeze. Do not shake. Do not use after the expiry date (EXP) shown on the pack.
For storage conditions after dilution of the medicine, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Gazyva 40 mL concentrate solution for infusion (25 mg/mL) in a sterile, preservative free, non-pyrogenic 50 mL vial (clear Type I glass).

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.

Gazyva (obinutuzumab) is a recombinant monoclonal humanised and glycoengineered type II anti-CD20 antibody of the IgG1 isotype.

CAS number.

CAS: 949142-50-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4. Prescription Only Medicine.

Summary Table of Changes