GAZYVARO 1000 MG CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet:information for the patient

Gazyvaro 1,000mg concentrate for solution for infusion

Obinutuzumab

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Gazyvaro and what is it used for
2. What you need to know before you use Gazyvaro
3. How to use Gazyvaro
4. Possible side effects
5. Storage of Gazyvaro
6. Contents of the pack and other information

1. What is Gazyvaro and what is it used for

What is Gazyvaro

Gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines called “monoclonal antibodies”. Antibodies work by targeting specific areas in our body.

What is Gazyvaro used for

Gazyvaro can be used in adults to treat two different types of cancer

• Chronic lymphocytic leukemia(also called “CLL”)

• Gazyvaro is used in patients who have not received any previous treatment for CLL and who have other diseases that make it unlikely that patients will be able to tolerate a full dose of a different medicine called fludarabine, used to treat CLL.
• Gazyvaro is used together with another cancer medicine called chlorambucil.

• Follicular lymphoma(also called “FL”)

• Gazyvaro is used in patients who have not received any treatment for FL.
• Gazyvaro is used in patients who have received at least one previous treatment with a medicine called rituximab or whose FL has come back or got worse during or after this treatment.
• At the start of FL treatment, Gazyvaro is used together with other cancer medicines.
• Gazyvaro may be used alone for up to 2 years as “maintenance treatment”.

How Gazyvaro works

• CLL and FL are types of cancer that affect the white blood cells called “B lymphocytes”. The affected “B lymphocytes” multiply too quickly and live too long.

Gazyvaro attaches to targets on the surface of the affected “B lymphocytes” and causes them to die.

• When Gazyvaro is given to patients with CLL or FL together with other cancer medicines, it delays the time it takes for their disease to get worse.

2. What you need to know before you use Gazyvaro

Do not use Gazyvaro:

• if you are allergic to obinutuzumab or any of the other ingredients of this medicine (listed in section 6).

If you are not sure, talk to your doctor or nurse before starting Gazyvaro.

Warnings and precautions

Talk to your doctor or nurse before starting Gazyvaro if:

• you have an infection, or have had a long-lasting or repeated infection in the past
• you have taken, or been given, medicines that affect your immune system (such as chemotherapy or immunosuppressive medicines)
• you are taking medicines for high blood pressure or medicines to thin your blood; your doctor may need to change how you are taking them
• you have had heart problems in the past
• you have had brain problems (such as memory problems, difficulty moving or feeling in your body, vision problems)
• you have had breathing or lung problems
• you have had hepatitis B - a type of liver disease
• you are due to have a vaccine or know you will need to have one soon.

If you are in any of these situations (or if you are not sure), talk to your doctor or nurse before starting Gazyvaro.

Look out for the following side effects

Gazyvaro can cause some serious side effects. You must tell your doctor or nurse immediately. These include:

Infusion-related reactions

• Tell your doctor or nurse immediately if you experience any infusion-related reactions, including those listed in section 4. Infusion-related reactions can occur during or up to 24 hours after the infusion.
• If you have infusion-related reactions, you may need extra treatment or your infusion rate may need to be slowed down or stopped. When these symptoms go away or get better, your infusion can continue. These reactions are more likely to happen during your first infusion. Your doctor may decide to stop your treatment with Gazyvaro if you have a serious infusion-related reaction.
• Before each infusion of Gazyvaro, you will be given medicines to help reduce the chance of infusion-related reactions or “tumor lysis syndrome”. Tumor lysis syndrome is a potentially life-threatening complication caused by chemical changes in the blood due to the breakdown of dying cancer cells (see section 3).

Progressive multifocal leukoencephalopathy (also called “PML”)

• PML is a very rare and potentially life-threatening brain infection that has been reported with the use of Gazyvaro.
• Tell your doctor or nurse immediately if you have memory loss, speech problems, difficulty walking or vision problems.
• If you had any of these symptoms before treatment with Gazyvaro, tell your doctor immediately if you notice any change in them. You may need medical treatment.

Infections

Tell your doctor or nurse immediately if you experience any signs of infection after treatment with Gazyvaro (see “Infections” in section 4).

Children and adolescents

Do not give Gazyvaro to children or adolescents under 18 years old. This is because there is no information on its use in these age groups.

Other medicines and Gazyvaro

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines.

Pregnancy

• Tell your doctor or nurse if you are pregnant, think you may be pregnant or are planning to have a baby. They will help you to make a decision on whether to continue with Gazyvaro, taking into account the benefits and risks to your baby.
• If you become pregnant during treatment with Gazyvaro, tell your doctor or nurse as soon as possible. This is because treatment with Gazyvaro may affect your health or that of your baby.

Breast-feeding

• Do not breast-feed your baby during treatment with Gazyvaro and for 18 months after finishing treatment with Gazyvaro. This is because small amounts of the medicine may pass into breast milk.

Contraception

• Use effective contraception during treatment with Gazyvaro.
• Continue to use effective contraception for 18 months after finishing treatment with Gazyvaro.

Driving and using machines

Gazyvaro is unlikely to affect your ability to drive, ride a bike or use tools or machines. However, if you have an infusion-related reaction (see section 4), do not drive, do not ride a bike and do not use machines until the reaction has passed.

3. How to use Gazyvaro

How Gazyvaro is given

Gazyvaro is given under the supervision of a doctor who is experienced in giving this treatment. It is given into a vein over several hours.

Gazyvaro treatment

Chronic lymphocytic leukemia

• You will be given 6 cycles of Gazyvaro treatment in combination with another cancer medicine called chlorambucil. Each cycle lasts 28 days.
• On day 1 of your first cycle, you will be given a small part of your first dose of Gazyvaro (100 mg) very slowly. Your doctor or nurse will watch you closely for infusion-related reactions.
• If you do not have any infusion-related reactions after the first part of your dose, you may be given the rest of your first dose (900 mg) on the same day.
• If you have an infusion-related reaction after the first part of your dose, you will be given the rest of your first dose on day 2.

The following is the usual schedule of administration.

Cycle 1 – includes three doses of Gazyvaro over 28 days:

• Day 1 – part of your first dose (100 mg)
• Day 2 or day 1 (continuation) – rest of your first dose (900 mg)
• Day 8 – full dose (1,000 mg)
• Day 15 – full dose (1,000 mg)

Cycles 2, 3, 4, 5 and 6 – one dose of Gazyvaro every 28 days:

• Day 1 – full dose (1,000 mg)

Follicular lymphoma

• You will be given 6 or 8 cycles of Gazyvaro treatment in combination with other cancer medicines. Each cycle lasts 28 or 21 days depending on which other cancer medicines are given with Gazyvaro.
• The “maintenance phase” will follow the induction phase. During this time, you will be given Gazyvaro every 2 months for up to 2 years, as long as your disease does not get worse. Depending on the state of your disease after the initial treatment cycles, your doctor will decide whether you will receive treatment in the maintenance phase.
• The following is the usual schedule of administration.

Induction phase

Cycle 1 – includes three doses of Gazyvaro over 28 or 21 days, depending on which other cancer medicines are given with Gazyvaro:

• Day 1 – full dose (1,000 mg)
• Day 8 – full dose (1,000 mg)
• Day 15 – full dose (1,000 mg)

Cycles 2, 6 or 2-8 – one dose of Gazyvaro every 28 or 21 days, depending on which other cancer medicines are given with Gazyvaro:

• Day 1 – full dose (1,000 mg)

Maintenance phase

• Full dose (1,000 mg) every 2 months for up to 2 years, as long as your disease does not get worse.

Medicines given before each infusion

Before each infusion of Gazyvaro, you will be given medicines to reduce the chance of infusion-related reactions or tumor lysis syndrome. These medicines may include:

• fluids
• medicines to reduce fever
• medicines to reduce pain (painkillers)
• medicines to reduce inflammation (corticosteroids)
• medicines to reduce an allergic reaction (antihistamines)
• medicines to prevent tumor lysis syndrome (such as allopurinol)

If you miss a dose of Gazyvaro

If you miss an appointment, make another one as soon as possible. To get the most benefit from your medicine, it is important to follow the planned schedule.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects have been reported with this medicine:

Serious side effects

Infusion-related reactions

Tell your doctor or nurse immediately if you experience any of the following symptoms during or up to 24 hours after your infusion.

Frequently reported reactions:

• nausea
• fatigue
• dizziness
• headache
• diarrhea
• fever, flushing or chills
• vomiting
• shortness of breath
• low or high blood pressure
• fast heart rate
• chest discomfort

Less frequently reported reactions:

• irregular heartbeats
• inflammation of the throat or airways
• wheezing, difficulty breathing, chest tightness or throat irritation

If you have any of the above symptoms, tell your doctor or nurse immediately.

Progressive multifocal leukoencephalopathy

PML is a very rare and potentially life-threatening brain infection that has been reported with the use of Gazyvaro.

Tell your doctor or nurse immediately if you have:

• memory loss
• speech problems
• difficulty walking
• vision problems

If you had any of these symptoms before treatment with Gazyvaro or if you notice any change in them, tell your doctor immediately. You may need medical treatment.

Infections

You may be more likely to get infections during and after treatment with Gazyvaro. These are usually colds, but there have been cases of more serious infections. There have also been reports of a type of liver disease called “hepatitis B” coming back in patients who had hepatitis B in the past.

Tell your doctor or nurse immediately if you experience any signs of infection during and after treatment with Gazyvaro. These include:

• fever
• cough
• chest pain
• fatigue
• painful rash
• sore throat
• burning when you urinate
• feeling weak or unwell

If you had repeated or long-lasting infections before starting treatment with Gazyvaro, tell your doctor.

Other side effects:

Tell your doctor or nurse if you experience any of the following side effects:

Very common (may affect more than 1 in 10 people)

• fever
• lung infection
• headache
• joint pain, back pain
• feeling weak
• feeling tired
• pain in arms and legs
• diarrhea, constipation
• insomnia
• hair loss, itching
• urinary tract infection, inflammation of the nose and throat, shingles

• changes in blood tests:

• anemia (low red blood cell count)
• low white blood cell count (including all types of white blood cells)
• low neutrophil count (a type of white blood cell)
• low platelet count (a type of blood cell that helps the blood to clot)

• infection of the upper airways (infection of the nose, throat, larynx and sinuses), cough

Common (may affect up to 1 in 10 people)

• cold sore
• depression, anxiety
• flu (influenza)
• weight gain
• runny nose or nasal congestion
• eczema
• pain in the mouth and throat
• muscle and bone pain in the chest
• skin cancer (squamous cell carcinoma, basal cell carcinoma)
• bone pain
• irregular heartbeats (atrial fibrillation)
• urination problems, urinary incontinence
• high blood pressure
• digestive problems (such as heartburn), hemorrhoids
• changes in blood tests with:

• low lymphocyte count (a type of white blood cell), fever associated with low neutrophil count (a type of white blood cell)
• high potassium, phosphate or uric acid, which can cause kidney problems (part of tumor lysis syndrome)
• low potassium

• hole in the stomach or intestines (gastrointestinal perforation, especially in cases where the cancer affects the gastrointestinal tubes)

Uncommon (may affect up to 1 in 100 people)

• abnormal blood clotting, including a serious condition in which blood clots form throughout the body (disseminated intravascular coagulation)
• changes in blood tests: low immunoglobulin levels (antibodies that help fight infections)

Tell your doctor or nurse if you experience any of the above side effects.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Gazyvaro

Healthcare professionals will store Gazyvaro in the hospital or clinic. The following storage conditions apply:

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of the month stated.
• Store in a refrigerator (2°C - 8°C). Do not freeze.
• Keep the vial in the outer packaging to protect it from light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Content and Additional Information

Composition of Gazyvaro

• The active ingredient is obinutuzumab: 1,000 mg/40 ml per vial corresponding to a concentration before dilution of 25 mg/ml.
• The other components are histidine, histidine hydrochloride monohydrate, trehalose dihydrate, poloxamer 188, and water for injectable preparations.

Appearance of the Product and Container Content

Gazyvaro is a concentrate for solution for infusion and is a colorless to slightly brown liquid. Gazyvaro is supplied in a container that contains 1 glass vial.

Marketing Authorization Holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Manufacturer

Roche Pharma AG

Emil-Barell-Strasse 1

D-79639 Grenzach-Wyhlen

Germany

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Prospectus:

Other Sources of Information

Detailed information about this medication is available on the European Medicines Agency website:https://www.ema.europa.eu.

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This information is intended only for healthcare professionals:

Dosage

Gazyvaro should be administered under the close supervision of an experienced physician, and in an environment that has immediate access to a complete resuscitation equipment.

Prophylaxis and premedication for tumor lysis syndrome (TLS)

Patients with high tumor burden and/or high lymphocyte count in circulation (>25 × 10^9/l) and/or renal insufficiency (ClCr < 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 alternative treatment such as urate oxidase (e.g., rasburicase), starting 12 to 24 hours before initiating Gazyvaro infusion, according to standard practice. All patients considered at risk should be carefully monitored during the first days of treatment, with special attention to renal function, potassium, and uric acid values. Any additional recommendations should be followed according to standard practice.

Prophylaxis and premedication for infusion-related reactions (IRRs)

Premedication to reduce the risk of IRRs is described in Table 1. Premedication with corticosteroids is recommended in patients with FL and is mandatory for patients with CLL in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

During intravenous infusions of Gazyvaro, the patient may present hypotension as a symptom of IRR. Therefore, consideration should be given to suspending antihypertensive treatments from 12 hours before, during each Gazyvaro infusion, and one hour after each Gazyvaro infusion.

Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of IRRs in patients with CLL and FL

1 100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone.

Hydrocortisone should not be administered as it has not been effective in reducing the rate of IRRs.

2 For example, 1,000 mg acetaminophen/paracetamol

3 For example, 50 mg diphenhydramine

4 If a chemotherapy regimen that includes a corticosteroid is administered on the same day as Gazyvaro, the corticosteroid may be administered as an oral medication, provided it is administered at least 60 minutes before Gazyvaro, in which case no additional intravenous corticosteroid is required as premedication.

Dosage

Chronic Lymphocytic Leukemia (in combination with chlorambucil)

The recommended dose of Gazyvaro in combination with chlorambucil for patients with CLL is shown in Table 2.

Cycle 1

The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 and Day 2 (or continuation of Day 1), and on Day 8 and Day 15 of the first 28-day treatment cycle. Two infusion bags should be prepared for Day 1 and Day 2 (100 mg for Day 1 and 900 mg for Day 2). If the infusion of the first bag is completed without modifying the infusion rate or without interruptions, the second bag may be administered on the same day (it is not necessary to postpone the dose or repeat the premedication), provided that the time is adequate and medical conditions and supervision are available during the entire infusion. If during the first 100 mg there is any modification of the infusion rate or interruption, the second bag should be administered the next day.

Cycles 2-6

The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle.

Table 2 Dose of Gazyvaro to be administered during 6 cycles of 28-day treatment each for patients with CLL

1 Chlorambucil is administered orally at 0.5 mg/kg body weight on Day 1 and Day 15 of all treatment cycles

Duration of Treatment

Six cycles of treatment, each lasting 28 days.

Follicular Lymphoma

For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown in Table 3.

Patient with previously untreated follicular lymphoma

Induction phase (in combination with chemotherapy)

Gazyvaro should be administered with chemotherapy as follows:

• Six 28-day cycles in combination with bendamustine or
• Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or
• Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisolone/prednisone/methylprednisolone (CVP).

Maintenance phase

Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy should continue to receive Gazyvaro 1,000 mg as monotherapy, as maintenance treatment every 2 months for 2 years or until disease progression (whichever occurs first)

Patient with follicular lymphoma who did not respond or progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen

Induction phase (in combination with bendamustine)

Gazyvaro should be administered in six 28-day cycles in combination with bendamustine

Maintenance phase

Patients who achieved a complete or partial response to induction treatment (i.e., the initial 6 cycles of treatment) with Gazyvaro in combination with bendamustine or who have stable disease should continue to receive Gazyvaro 1,000 mg alone, as maintenance therapy every 2 months for 2 years or until disease progression (whichever occurs first)

Table 3 Follicular lymphoma: Dose of Gazyvaro to be administered during induction treatment, followed by maintenance treatment

2 Bendamustine is administered intravenously on Days 1 and 2 of all treatment cycles (Cycles 1 to 6) at 90 mg/m^2/day; CHOP and CVP according to standard regimens

Duration of Treatment

Induction treatment of approximately 6 months (six cycles of Gazyvaro treatment, each lasting 28 days when combined with bendamustine, or eight cycles of Gazyvaro treatment, each lasting 21 days when combined with CHOP or CVP) followed by maintenance treatment every 2 months for 2 years or until disease progression (whichever occurs first)

Method of Administration

Gazyvaro is administered intravenously. It should be administered after dilution as an intravenous infusion using a dedicated line. Gazyvaro infusions should not be administered as rapid infusion or intravenous bolus.

For instructions for dilution prior to administration of Gazyvaro, see below.

Tables 4-6 provide instructions on infusion rates.

Chronic Lymphocytic Leukemia

Table 4 Chronic Lymphocytic Leukemia: Standard Infusion Rate in the absence of IRR/Hypersensitivity to Infusion and recommendations in case of previous IRR

Follicular Lymphoma (FL)

Gazyvaro should be administered at a standard infusion rate in Cycle 1 (see Table 5). In patients who do not present a Grade ≥3 infusion-related reaction during Cycle 1, Gazyvaro can be administered as a short-duration infusion (SDI) (approximately 90 minutes) from Cycle 2 onwards (see Table 6).

Table 5 Follicular Lymphoma: Standard Infusion Rate and recommendations in case of previous IRR with infusion

Table 6

Management of IRRs (all indications)

The management of IRRs may require temporary interruption, reduction of the infusion rate, or discontinuation of treatment with Gazyvaro, as described below.

• Grade 4 (potentially life-threatening): infusion should be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion should be temporarily stopped and symptoms treated. Once symptoms have resolved, infusion can be restarted at a rate not exceeding half of the previous rate (i.e., the rate being used at the time of the IRR) and, if the patient does not experience any IRR symptoms, the infusion rate can be increased to the increments and intervals that are appropriate for the treatment dose (see Tables 4-6). For patients with CLL receiving the Day 1 (Cycle 1) dose divided over two days, the infusion rate on Day 1 can be increased up to 25 mg/h after 1 hour, but not increased further.

If the patient experiences a second Grade 3 IRR, infusion should be stopped and treatment permanently discontinued.

• Grade 1-2 (mild to moderate): infusion rate can be reduced and symptoms treated. Infusion can be continued once symptoms have resolved and, if the patient does not experience any IRR symptoms, the infusion rate can be increased to the increments and intervals that are appropriate for the treatment dose (see Tables 4-6). For patients with CLL receiving the Day 1 (Cycle 1) dose divided over two days, the infusion rate on Day 1 can be increased up to 25 mg/h after 1 hour, but not increased further.

Management of IRRs Occurring During PCD

• Grade 4 (potentially life-threatening): infusion should be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion should be temporarily stopped and symptoms treated. Once symptoms have resolved, infusion can be restarted at a rate not exceeding half of the previous rate (i.e., the rate being used at the time of the IRR) and not exceeding 400 mg/h.

If the patient experiences a second Grade 3 IRR after restarting infusion, infusion should be stopped and treatment permanently discontinued. If the patient is able to complete the infusion without further Grade 3 reactions, the next infusion should be administered at a rate not exceeding the standard rate.

• Grade 1-2 (mild to moderate): infusion rate can be reduced and symptoms treated. Infusion can be continued once symptoms have resolved and, if the patient does not experience any IRR symptoms, the infusion rate can be increased to the increments and intervals that are appropriate for the treatment dose (see Tables 5-6).

Dilution Instructions

Gazyvaro should be prepared by a healthcare professional under aseptic conditions. Do not shake the vial. Use a sterile needle and syringe to prepare Gazyvaro.

For Cycles 2-6 in patients with CLL and for all cycles in patients with FL

Withdraw 40 ml of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/ml (0.9%) injection solution.

Cycle 1 - only in patients with CLL

For the initial dose of 1,000 mg to distinguish between the two infusion bags, it is recommended to use infusion bags of different sizes to differentiate between the 100 mg dose for Day 1 of Cycle 1 and the 900 mg dose for Day 1 (continuation) or Day 2 of Cycle 1. To prepare the two infusion bags, withdraw 40 ml of concentrate from the vial and dilute 4 ml in a 100 ml PVC or non-PVC polyolefin infusion bag and the remaining 36 ml in a 250 ml PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/ml (0.9%) injection solution. Clearly label each infusion bag.

No incompatibilities have been observed between Gazyvaro at concentrations of 0.4 mg/ml to 20 mg/ml after dilution of Gazyvaro in sodium chloride 9 mg/ml (0.9%) injection solution and:

• PVC, polyethylene (PE), polypropylene, or polyolefin bags
• PVC, polyurethane (PUR), or PE infusion sets
• Optional in-line filters with product contact surfaces made of polyethersulfone (PES), a three-way valve made of polycarbonate (PC), and catheters made of polyurethane (PEU).

Do not use other diluents, such as glucose 5% solution.

The bag should be gently inverted to mix the solution in order to avoid excessive foam formation. The diluted solution should not be shaken or frozen.

Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration.

After dilution, chemical and physical stability has been demonstrated in sodium chloride 9 mg/ml (0.9%) injection solution at concentrations of 0.4 mg/ml to 20 mg/ml for 24 hours at a temperature between 2°C and 8°C followed by 48 hours (including infusion time) at a temperature ≤30°C.

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and normally should not exceed 24 hours at 2°C to 8°C, unless the dilution has been performed in controlled and validated aseptic conditions.

Disposal

Disposal of unused medicinal products and all materials that have come into contact with them should be done in accordance with local regulations.