Gazyvaro 1000 mg concentrado para solucion para perfusion

Prospecto:information for the patient

Gazyvaro 1.000mg concentrate for solution for infusion

Obinutuzumab

Read this prospectus carefully before starting to use this medication, because it contains important information for you.

• Keep this prospectus,as you may need to read it again.
• If you have any doubts, consult your doctor or nurse.
• If you experience adverse effects, consult your doctor or nurse,even if they are not listed in this prospectus.See section 4.

What is Gazyvaro

Gazyvaro contains the active ingredient obinutuzumab, which belongs to a group of medicines called “monoclonal antibodies”. Monoclonal antibodies act by attacking specific targets 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 known as “CLL”)

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

• Follicular Lymphoma(also known as “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 recurred or worsened during or after this treatment.
• At the start of FL treatment, Gazyvaro is used in combination with other cancer medicines.
• Gazyvaro can be used alone for a maximum of 2 years as “maintenance treatment”.

How Gazyvaro works

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

Gazyvaro binds to targets on the surface of the affected “B lymphocytes” and causes their death.

• When Gazyvaro is administered to patients with CLL or FL in combination with other cancer medicines, the time of disease progression is delayed.

No use Gazyvaro:

• ifyou are allergic to obinutuzumab or any of the other components of this medication (listed in section 6).

If you are unsure, consult your doctor or nurse before starting Gazyvaro.

Warnings and precautions

Consult your doctor or nurse before starting Gazyvaroif:

• you have an infection, or have had a prolonged or recurring infection in the past
• you have taken or been given medications that affect your immune system (such as chemotherapy or immunosuppressive medications)
• you are taking medications for hypertension or medications to reduce blood thickness; your doctor may need to modify how you are using them
• you have had previous heart problems
• you have had previous neurological problems (such as memory problems, difficulty moving, or sensitivity in the body, vision problems)
• you have had previous respiratory or pulmonary problems
• you have had previous hepatitis B - a type of liver disease
• you are due to receive avaccine or know that you will need one in the near future.

If you are in any of the above situations (or are unsure), consult your doctor or nurse before starting Gazyvaro.

Be aware of the following adverse effects

Gazyvaro may cause some serious adverse effects. You must inform your doctor or nurse immediately. These include:

Infusion-related reactions

• Inform your doctor or nurse immediately if you experience any infusion-related reactions, including those listed in section 4. Infusion-related reactions can occur during infusion or up to 24 hours after it.
• If you experience infusion-related reactions, you may require additional treatment or the infusion rate may need to be reduced or stopped.When these symptoms resolve or improve, the infusion can be continued.It is more likely that these reactions will occur during the first infusion.Your doctor may decide to interrupt Gazyvaro treatment if you experience a severe infusion-related reaction.
• Before each Gazyvaro infusion, you will be given medications to help reduce possible infusion-related reactions or "tumor lysis syndrome". Tumor lysis syndrome is a potentially fatal complication caused by chemical changes in the blood due to the breakdown of cancer cells (see section 3).

Progressive multifocal leukoencephalopathy (also known as "LMP")

• LMP is a rare and potentially fatal brain infection that has been associated with Gazyvaro use.
• Inform your doctor or nurse immediately if you experience memory loss, speech problems, difficulty walking, or vision problems.
• If you experienced any of these symptoms before starting Gazyvaro treatment, inform your doctor immediately if you notice any change in them. You may require medical treatment.

Infections

Inform your doctor or nurse immediately if you experience any signs of infection after Gazyvaro treatment (see "Infections" in section 4).

Children and adolescents

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

Other medications and Gazyvaro

Inform your doctor or nurse if you are taking, have taken recently, or may need to take any other medication.This includes over-the-counter medications and herbal medications.

Pregnancy

• Inform your doctor or nurse if you are pregnant, think you may be pregnant, or intend to become pregnant. They will help you evaluate the benefit of continuing Gazyvaro treatmentagainst the risk to your baby.
• If you become pregnant during Gazyvaro treatment, inform your doctor or nurse as soon as possible. This is because Gazyvaro treatment may affect your health or that of your baby.

Breastfeeding

• Do not breastfeed your baby during Gazyvaro treatment or for 18 months after completing Gazyvaro treatment. This is because small amounts of the medication may pass into breast milk.

Contraception

• Use an effective contraceptive method during Gazyvaro treatment.
• Continue using an effective contraceptive method for 18 months after completing Gazyvaro treatment.

Driving and operating machinery

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

How Gazyvaro is administered

Gazyvaro is administered under the supervision of an experienced doctor.It is administered intravenously as a drip (intravenous infusion) over several hours.

Gazyvaro treatment

Chronic lymphocytic leukemia

• You will receive 6 cycles of Gazyvaro treatment in combination with another cancer medication, called chlorambucil. Each cycle lasts 28 days.
• On day 1 of your first cycle, you will receive a slow infusion of part of your first dose of Gazyvaro, 100 mg. Your doctor or nurse will closely monitor you for infusion-related reactions.
• If you do not experience any infusion-related reactions after the first part of your dose, it is possible that you will receive the rest of your first dose (900 mg) on the same day.
• If you experience an infusion-related reaction after the first part of your dose, you will receive the rest of your first dose on day 2.

The following is the normal administration schedule.

Cycle 1 – includes three doses of Gazyvaro in 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 – a single dose of Gazyvaro in 28 days:

• Day 1 – full dose (1,000 mg)

Follicular lymphoma

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

Induction phase

Cycle 1– includes three doses of Gazyvaro in 28 days or 21 days, depending on which other cancer medications are administered with Gazyvaro:

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

Cycles2, 6, or 2-8 – a single dose of Gazyvaro in 28 days or 21 days, depending on which other cancer medications are administered with Gazyvaro:

• Day 1 – full dose (1,000 mg)

Maintenance phase

• Full dose (1,000 mg) every 2 monthsfor up to 2 years, as long as your disease does not progress.

Medications administered before each infusion

Before each infusion of Gazyvaro, you will receive medications to reduce the risk of infusion-related reactions or tumor lysis syndrome. These medications may include:

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

If you forget to take Gazyvaro

If you miss a dose, reschedule as soon as possible. To ensure the medication is as effective as possible, it is essential to follow the established administration schedule.

If you have any questions about the use ofthis medication, consult your doctor or nurse.

Like all medicines, this medicine canproduce side effects, although not everyone will experience them.The following side effects have been reported with this medicine:

Severe side effects

Perfusion-related reactions

Inform your doctor or nurse immediately if you experience any of the following symptoms during perfusion or within 24 hours after perfusion.

Commonly reported side effects:

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

Less commonly reported side effects:

• irregular heartbeats
• throat or respiratory tract inflammation
• whistling, difficulty breathing, chest tightness, or throat irritation

If you experience any of the above symptoms, inform your doctor or nurse immediately.

Progressive multifocal leukoencephalopathy

PML is a rare and potentially fatal brain infection that has been reported with the use of Gazyvaro.

Inform your doctor or nurse immediately if you experience:

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

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

Infections

You may be more likely to contract infections during and after treatment with Gazyvaro.Often, these are colds, but there have been cases of more serious infections.There have also been reports of reactivation of a type of liver disease called "hepatitis B" in patients who had hepatitis B previously.

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

• fever
• cough
• chest pain
• fatigue
• painful rash
• sore throat
• burning sensation while urinating
• general feeling of weakness or discomfort.

If you had recurrent or chronic infections before starting treatment with Gazyvaro, inform your doctor.

Other side effects:

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

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

• fever
• pneumonia
• headache
• joint or back pain
• weakness
• fatigue
• pain in arms and legs
• diarrhea, constipation
• insomnia
• hair loss, itching
• urinary tract infection, nasal and throat inflammation, herpes zoster

• changes in blood test results:

• anemia (low red blood cell count)
• low white blood cell count (combined)
• low neutrophil count (a type of white blood cell)
• low platelet count (a type of blood cell that helps blood clot)

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

Common (may affect up to 1 in 10 people)

• cold sores
• depression, anxiety
• influenza
• weight gain
• runny nose or nasal congestion
• eczema
• mouth and throat pain
• chest muscle and bone pain
• skin cancer (squamous cell carcinoma, basal cell carcinoma)
• bone pain
• irregular heartbeats (atrial fibrillation)
• urination problems, incontinence
• high blood pressure
• digestive problems (e.g. heartburn), hemorrhoids
• changes in blood test results 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 levels, which can cause kidney problems (part of the tumor lysis syndrome)
• low potassium levels

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

Rare (may affect up to 1 in 100 people)

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

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

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse,even if it is a possible side effect that does not appear in this leaflet.You can also report them directly through thenational reporting system included in theAppendix V.By reporting side effects, you can contribute to providing more information about the safety of this medicine.

Healthcare professionals will conserve Gazyvaro in the hospital or clinic.The following storage conditions are detailed below:

• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the packaging after CAD.The expiration date is the last day of the month indicated.
• Store in a refrigerator (between 2°C and 8°C). Do not freeze.
• Keep the vial in the outer packaging to protect it from light.

Medicines should not be disposed of through drains or in the trash.Ask your pharmacist how to dispose of the packaging and medications that you no longer need.This will help protect the environment.

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, hydrochloride of histidine monohydrate, trehalose dihydrate, poloxamer 188, and water for injection preparations.

Appearance of the product and contents of the package

Gazyvaro is a concentrate for solution for infusion and is a colorless to slightly brown liquid.Gazyvaro is supplied in a package containing 1 glass vial.

Marketing Authorization Holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Responsible for manufacturing

Roche Pharma AG

Emil-Barell-Strasse 1

D-79639 Grenzach-Wyhlen

Germany

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Last update of this leaflet:

Other sources of information

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

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This information is intended solely for healthcare professionals:

Dosage

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

Prophylaxis and premedication for the Hematologic Toxicity (HT) syndrome

Patients with a high tumor burden and/or a high circulating lymphocyte count (>25 × 10^9/l) and/or renal insufficiency (ClCr <70 ml min) are considered at risk of ht and should receive prophylaxis. prophylaxis consist adequate hydration administration uricostatics (e.g., allopurinol), or an alternative suitable treatment such as uricase oxidase rasburicase), starting 12 to 24 hours before initiating gazyvaro infusion according standard practice.< span>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 levels. 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. Corticosteroid premedication is recommended for patients with lymphocytopenia and is mandatory for patients with lymphopenia in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

During Gazyvaro intravenous infusions, the patient may experience hypotension as a symptom of IRR.Therefore, consideration should be given to suspending antihypertensive treatments from 12 hours before, during each infusion with Gazyvaro, and 1 hour after each infusion of Gazyvaro.

Table 1Premedication that should be administered before Gazyvaro infusion to reduce the risk of IRRs in patients with lymphopenia and lymphocytopenia

1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg of methylprednisolone.

Do not administer hydrocortisone as it has not been effective in reducing the rate of IRRs.

2For example, 1,000 mg of acetaminophen/paracetamol

3For example, 50 mg of diphenhydramine

4If 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 IV corticosteroid premedication is required.

Dose

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 first infusion bag is completed without modification of the infusion rate or interruptions, the second infusion bag may be administered on the same day (no need to postpone the dose or repeat premedication), provided the time is adequate, and medical supervision and conditions are available throughout the infusion. If there are any modifications to the infusion rate or interruptions during the first 100 mg, the second infusion 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 2Dose of Gazyvaro that should be administered during 6 cycles of 28-day treatment for patients with CLL

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

Treatment duration

Six cycles of treatment, each 28 days in duration.

Follicular Lymphoma

The recommended dose of Gazyvaro in combination with chemotherapy for patients with FL is shown in Table 3.

Patients with previously untreated follicular lymphoma

Induction phase (in combination with chemotherapy 2)

Gazyvaro should be administered with chemotherapy as follows:

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

Maintenance phase

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

Patients with follicular lymphoma who did not respond or progressed during or until 6 months after treatment with rituximab or a regimen containing rituximab

Induction phase (in combination with bendamustine 2)

Gazyvaro should be administered in six cycles of 28 days in combination with bendamustine 2.

Maintenance phase

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

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

2Bendamustine 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

Treatment duration

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

Administration form

Gazyvaro should be administered intravenously. It should be administered after dilution as an intravenous infusion using a specific infusion set.The infusions of Gazyvaro should not be administered as a rapid infusion or as a bolus intravenous injection.

For the instructions for the previous dilution before administration of Gazyvaro, see below.

The infusion rates are indicated in Tables 4-6.

Chronic Lymphocytic Leukemia

Table 4Chronic lymphocytic leukemia: Standard infusion rate in the absence of IRR/infusion-related hypersensitivity and recommendations in case of IRR with the previous infusion

Follicular Lymphoma (FL)

Gazyvaro should be administered at standard infusion rate in Cycle 1 (see Table 5). In patients who do not experience IRR Grade ≥3 during Cycle 1, Gazyvaro may be administered as a short infusion (SI) (approximately 90 minutes) from Cycle 2 onwards (see Table 6).

Table 5Follicular lymphoma: Standard infusion rate and recommendations in case of IRR with the previous infusion

Table 6Follicular lymphoma: Short infusion and recommendations in case of IRR with the previous infusion

Management of IRRs (all indications)

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

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

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

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

Management of IRRs produced during SI

• Grade 4 (potentially fatal):infusion should be stopped and treatment with Gazyvaro should be permanently discontinued.
• Grade 3 (severe): infusion should be temporarily stopped and symptoms should be treated.Once symptoms are resolved, infusion may be restarted at a rate that does not exceed half the previous rate (i.e., the rate being used at the time the IRR occurred) and not greater than 400 mg/h.

If the patient experiences a second IRR Grade 3 after reinitiating infusion, infusion should be stopped and treatment with Gazyvaro should be 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 may be reduced and symptoms should be treated.Infusion may be continued once symptoms are resolved and, if the patient does not experience any symptoms of IRR, infusion rate may be increased to the increments and intervals that are appropriate for the treatment dose (see Tables 5-6).

Instructions for dilution

Gazyvaro should be prepared by a healthcare professional in aseptic conditions. Do not agitate 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 infusion bags of polyvinyl chloride (PVC) or polyolefin without PVC that contain