Gazyvaro

Package leaflet: Information for the patient

Gazyvaro 1000 mg concentrate for solution for infusion

obinutuzumab
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

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

Contents of this leaflet

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

1. What Gazyvaro is and what it is used for

What Gazyvaro is
Gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines known as monoclonal antibodies. Antibodies work by binding to specific targets in the body.

What Gazyvaro is used for
This medicine is used in adults to treat several conditions. These include:

• Chronic Lymphocytic Leukemia (CLL)
  • Gazyvaro is used to treat adult patients who have not received prior treatment and who have other medical conditions making it unlikely that they would tolerate full-dose therapy with another medicine used to treat CLL called fludarabine.
  • Gazyvaro is used in combination with another anticancer medicine called chlorambucil.
• Follicular Lymphoma (FL)
  • Gazyvaro is used in patients who have not received any prior treatment for FL.
  • Gazyvaro is used to treat adult patients who have received at least one prior treatment with a medicine called rituximab and whose FL has returned or worsened during or after that treatment.
  • At the beginning of FL treatment, Gazyvaro is used in combination with other anticancer medicines.
  • Gazyvaro may subsequently be used alone for up to 2 years as maintenance therapy.
• Lupus Nephritis (LN)
  • Gazyvaro is used in combination with mycophenolate mofetile (MMF) to treat adult patients with active Class III or IV LN, with or without concomitant Class V (kidney inflammation caused by lupus).

How Gazyvaro works

• CLL and FL are types of blood cancer affecting white blood cells called B-lymphocytes. The affected B-lymphocytes multiply too quickly and live too long. Gazyvaro binds to specific targets on the surface of B-lymphocytes, causing their death.
  • When Gazyvaro is given to patients with CLL and FL in combination with other anticancer medicines, it slows down disease progression.
• LN is a type of kidney disease in which the body’s immune system mistakenly attacks the kidneys.
  • Gazyvaro reduces the number of B-lymphocytes, a type of immune system cell involved in causing some of the symptoms of LN.
  • Gazyvaro is given to patients with LN together with other medicines. This slows down or prevents the immune system from attacking healthy kidney cells.

2. What you should know before Gazyvaro is administered

Do not be given Gazyvaro if:

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

If you have any doubts, consult your doctor or nurse before receiving Gazyvaro.
Warnings and precautions
Talk to your doctor or nurse before receiving Gazyvaro if:

• you have an infection or have had an infection in the past that lasted a long time or recurred repeatedly;
• you have taken or have previously been given medicines that affect the immune system (such as chemotherapy medicines or immunosuppressants);
• you are taking medicines used to treat high blood pressure or to thin the blood – your doctor may need to adjust how you take them;
• you have previously had heart problems;
• you have previously had brain problems (such as memory problems, movement difficulties or sensory problems, vision problems);
• you have previously had breathing or lung problems;
• you have previously had hepatitis B, a type of liver disease.

If any of these conditions apply to you or if you are unsure, talk to your doctor or nurse before
Gazyvaro is administered.
Also talk to your doctor if you think you may need a vaccination in the near future,
including vaccines required for travel to other countries. Some vaccines should not be given
at the same time as Gazyvaro or in the months following treatment with Gazyvaro. Your doctor
will check whether you need to be vaccinated before starting treatment with Gazyvaro.
Be alert to the following side effects
Gazyvaro can cause some serious side effects that must be reported immediately to your doctor or
nurse. These include:
Infusion-related reactions

• Inform your doctor or nurse immediately if you develop any of the infusion-related reactions listed at the beginning of section 4. Infusion-related reactions may occur during infusion or within 24 hours after infusion.
• If you develop an infusion-related reaction, you may need additional treatment, or it may be necessary to slow down or stop the infusion. Once these symptoms have disappeared or subsided, the infusion may continue. The likelihood of developing these reactions is higher during the first infusion. If you experience a severe infusion-related reaction, your doctor may decide to discontinue treatment with Gazyvaro.
• Before each Gazyvaro infusion, you will be given medicines that help reduce the risk of possible infusion-related reactions or tumor lysis syndrome. Tumor lysis syndrome is a complication that can be fatal, caused by chemical changes in the blood due to the breakdown of dying tumor cells (see section 3).

Progressive multifocal leukoencephalopathy (PML)

• PML, a very rare brain infection that can be fatal, has been reported with the use of Gazyvaro.
• Inform your doctor or nurse immediately if you notice memory loss, difficulty speaking, difficulty walking, or vision loss.
• If you experienced any of these symptoms before treatment with Gazyvaro, inform your doctor immediately if you notice any changes, as you may require medical care.

Infections

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

Children and adolescents
Do not administer Gazyvaro to children or adolescents under 18 years of age, as there is no
information on its use in this age group.
Other medicines and Gazyvaro
Inform your doctor or nurse if you are taking, have recently taken, or might need to take any other
medicines, including those obtained without a prescription and herbal medicines.
Pregnancy

• Inform your doctor or nurse if you are pregnant, suspect you may be pregnant, or are planning a pregnancy. They will help you assess the benefits to you and the risks to the unborn child associated with taking Gazyvaro during pregnancy.
• If you become pregnant during treatment with Gazyvaro, inform your doctor or nurse as soon as possible, as treatment with Gazyvaro may affect your health or that of the unborn child.

Breast-feeding

• Gazyvaro may pass into breast milk in small amounts; therefore, you must not breast-feed during treatment with this medicine and for 18 months after stopping treatment with Gazyvaro.

Contraception

• Use an effective method of contraception during treatment with Gazyvaro.
• Continue using an effective method of contraception for 18 months after stopping treatment with Gazyvaro.

Driving and using machines
It is unlikely that Gazyvaro will affect your ability to drive, ride a bicycle, or use tools or
machinery. However, if you develop an infusion-related reaction (see section 4),
do not drive, ride a bicycle, or use tools or machinery until the reaction has resolved.

3. How Gazyvaro is administered

How Gazyvaro is administered
Gazyvaro is usually administered under the supervision of a physician experienced in this type of treatment. The medicine is given intravenously by infusion (intravenous infusion) over several hours.

Treatment with Gazyvaro
Chronic Lymphocytic Leukemia (CLL)

• You will receive 6 treatment cycles of Gazyvaro in combination with another anticancer medicine called chlorambucil. Each cycle lasts 28 days.
• On Day 1 of the first cycle, you will receive the first dose of Gazyvaro at 100 milligrams (mg) via a very slow infusion. Your doctor or nurse will monitor you closely for any infusion-related reactions.
• If you do not experience any infusion-related reaction during the administration of the initial small dose, the remaining portion of the first dose will be given on the same day.
• If you experience an infusion-related reaction during the initial small dose, the remaining portion of the first dose will be administered on Day 2.

The typical dosing schedule is outlined below.
Cycle 1 – this will include three doses of Gazyvaro within 28 days:

• Day 1 – initial portion (100 mg)
• Day 2 or continuation on Day 1 – remaining portion (900 mg)
• Day 8 – full dose (1,000 mg)
• Day 15 – full dose (1,000 mg)

Cycles 2, 3, 4, 5, and 6 – each will include only one dose of Gazyvaro within 28 days:

• Day 1 – full dose (1,000 mg)

Follicular Lymphoma (FL)

• You will receive 6 or 8 treatment cycles of Gazyvaro in combination with other anticancer medicines. Each cycle lasts 28 or 21 days, depending on the other anticancer medicines administered together with Gazyvaro.
• This induction treatment will be followed by a maintenance phase, during which Gazyvaro will be administered every 2 months for up to 2 years or until disease progression. Based on your disease status after the initial treatment cycles, your doctor will determine whether you will continue treatment during the maintenance phase.
• The typical dosing schedule is as follows.

Induction phase
Cycle 1 – this will include three doses of Gazyvaro within 28 or 21 days, depending on the other anticancer medicines administered together 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 – each will include only one dose of Gazyvaro within 28 or 21 days, depending on the other anticancer medicines administered together with Gazyvaro:

• Day 1 – full dose (1,000 mg)

Maintenance phase

• Full dose (1,000 mg) once every 2 months for up to 2 years or until disease progression.

Lupus Nephritis (LN)
You will receive 1,000 mg doses of Gazyvaro by intravenous infusion according to the following schedule:

• Dose 1 (initial infusion): 1,000 mg
• Dose 2 (Week 2, two weeks after Dose 1): 1,000 mg
• Dose 3 (Week 24): 1,000 mg
• Dose 4 (Week 26, two weeks after Dose 3): 1,000 mg
• Dose 5 (six months after Dose 4 and every six months thereafter): 1,000 mg

Medicines administered before each infusion
Before each Gazyvaro infusion, you will be given medicines to help reduce the risk of possible infusion-related reactions or tumor lysis syndrome. These may include:

• fluids
• medicines to reduce fever (antipyretics)
• medicines to relieve or eliminate pain (analgesics)
• medicines to reduce inflammation (corticosteroids)
• medicines to reduce the risk of allergic reactions (antihistamines)
• medicines to prevent tumor lysis syndrome (such as allopurinol)

If you miss a Gazyvaro treatment
If you miss an appointment for your infusion, ask your doctor when to schedule the next dose. It is extremely important to follow the dosing schedule exactly for this medicine to be fully effective.
If you have any questions about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. The following side effects have been reported with this medicine:
A. If you are being treated for chronic lymphocytic leukemia (CLL) or follicular lymphoma (FL)
Serious side effects
Infusion-related reactions
Tell your doctor or nurse immediately if you develop any of the following symptoms during or within 24 hours after the infusion:
More frequently reported:

• nausea
• fatigue
• dizziness
• headache
• diarrhea
• fever, flushing, or chills
• vomiting
• shortness of breath
• low or high blood pressure
• very rapid heartbeat
• chest discomfort

Less frequently reported:

• irregular heartbeat
• swelling of the throat or airways
• wheezing, difficulty breathing, chest tightness, or throat irritation

If you notice any of the above side effects, tell your doctor or nurse immediately.
Progressive multifocal leukoencephalopathy (PML)
PML, a very rare and potentially life-threatening brain infection, has been reported with the use of Gazyvaro.
Tell your doctor or nurse immediately if you notice any of the following side effects:

• memory loss
• difficulty speaking
• difficulty walking
• vision problems

If you experienced any of these symptoms before treatment with Gazyvaro, inform your doctor immediately if you notice any changes. You may require medical treatment.
Infections
During and after treatment with Gazyvaro, you may be more likely to get infections. Often these are simple colds, but more severe infections have also been reported. In patients who previously had hepatitis B, reactivation of the disease affecting the liver has been reported.
Tell your doctor or nurse immediately if you notice any signs of infection during or after treatment with Gazyvaro. These include:

• fever
• cough
• chest pain
• fatigue
• painful rash
• sore throat
• burning sensation when urinating
• feeling weak or generally unwell

If you experience any of these signs after treatment with Gazyvaro, tell your doctor or nurse immediately. If you had recurrent infections or long-lasting infections before starting treatment with Gazyvaro, inform your doctor or nurse.
Other side effects
Tell your doctor or nurse if you notice 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 nose and throat, shingles (herpes zoster)
• changes in blood tests:
  • anemia (low red blood cell levels)
  • low levels of all types of white blood cells (combined)
  • low levels of neutrophils (a type of white blood cell)
  • low platelet count (a type of blood cell that helps blood to clot)
• upper respiratory tract infection (infection of nose, pharynx, larynx, and sinuses), cough

Common (may affect up to 1 in 10 people)

• cold sores (herpes labialis)
• depression, anxiety
• influenza
• weight gain
• runny or stuffy nose
• eczema
• mouth or throat pain
• chest muscle and bone pain
• skin cancer (squamous cell carcinoma, basal cell carcinoma)
• bone pain
• irregular heartbeat (atrial fibrillation)
• problems urinating, urinary incontinence
• high blood pressure
• digestive problems (e.g., indigestion), hemorrhoids
• changes in blood tests:
  • low lymphocyte levels (a type of white blood cell), fever associated with low neutrophil levels (a type of white blood cell)
  • increased levels of potassium, phosphate, or uric acid, which may cause kidney problems (part of tumor lysis syndrome)
  • decreased potassium levels
• hole in the stomach or intestine (gastrointestinal perforation, especially in cases where cancer affects the gastrointestinal tract)

Uncommon (may affect up to 1 in 100 people)

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

Tell your doctor or nurse if you notice any of the side effects listed above.
B. If you are being treated for lupus nephritis (LN)
Serious side effects
Infections
During and after treatment with Gazyvaro, you may be more likely to get infections. Often these are simple colds, but more severe infections have also been reported.
Tell your doctor or nurse immediately if you notice any signs of infection during or after treatment with Gazyvaro. These include:

• sneezing
• runny or stuffy nose, postnasal drip
• fever
• cough
• chest pain
• fatigue
• rash
• sore throat
• burning sensation when urinating
• flu-like symptoms, feeling weak or generally unwell

If you experience any of these signs after treatment with Gazyvaro, tell your doctor or nurse immediately.
If you had recurrent or long-lasting infections before starting treatment with Gazyvaro, inform your doctor or nurse.
Neutropenia
Neutropenia involves low levels of neutrophils (a type of white blood cell) in the blood. Tell your doctor or nurse immediately if you notice any of the following side effects:

• fever or chills
• cough
• sore throat
• mouth ulcers due to infections
• changes in blood tests

Infusion-related reactions
Tell your doctor or nurse immediately if you develop any of the following symptoms during the infusion or within 24 hours after the infusion:

• nausea
• fatigue
• dizziness or fainting
• headache
• diarrhea
• fever, flushing, or chills
• vomiting
• shortness of breath or difficulty breathing
• low or high blood pressure
• very rapid heartbeat
• chest discomfort
• abdominal pain or discomfort
• redness, swelling, or discharge
• joint pain, muscle pain

Progressive multifocal leukoencephalopathy (PML)
PML, a very rare and potentially life-threatening brain infection, has been reported with the use of Gazyvaro in other indications.
Tell your doctor or nurse immediately if you notice any of the following side effects:

• memory loss
• difficulty speaking
• difficulty walking
• vision problems

If you experienced any of these symptoms before treatment with Gazyvaro, inform your doctor immediately if you notice any changes. You may require medical treatment.
Other side effects
Tell your doctor or nurse if you notice any of the following side effects:
Very common (may affect more than 1 in 10 people)

• lung inflammation (bronchitis)
• changes in blood tests: low levels of immunoglobulins (antibodies that help fight infections)

Common (may affect up to 1 in 10 people)

• lung infection (pneumonia)
• viral infection with herpes simplex of the mouth (such as cold sores) or genitals

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Gazyvaro

Gazyvaro will be stored by healthcare professionals at the hospital or clinic. The storage instructions are as follows.

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date stated on the packaging after "Exp./EXP". The expiry date refers to the last day of that month.
• Store in a refrigerator (2°C–8°C). Do not freeze.
• Keep the container in the outer packaging to protect the medicine from light.

Do not dispose of any medicine via wastewater or household waste. Healthcare professionals will dispose of unused medicines. This will help protect the environment.

6. Package contents and other information

What Gazyvaro contains

• The active substance is obinutuzumab: 1,000 mg/40 mL per vial, corresponding to a concentration of 25 mg/mL prior to dilution.
• The other ingredients are histidine, histidine monohydrochloride monohydrate, trehalose dihydrate, poloxamer 188 and water for injections.

Description of the appearance of Gazyvaro and contents of the pack
Gazyvaro is a concentrate for solution for infusion and is a liquid ranging from colourless to slightly brown. Gazyvaro is available in packs containing 1 glass vial.

Marketing Authorisation Holder
Roche Registration GmbH
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

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

België/Belgique/Belgien, Latvija
Luxembourg/Luxemburg Roche Latvija SIA
N.V. Roche S.A. Tel: +371 - 6 7039831
België/Belgique/Belgien
Tél/Tel: +32 (0) 2 525 82 11

България Lietuva
Рош България ЕООД UAB “Roche Lietuva”
Тел: +359 2 474 5444 Tel: +370 5 2546799

Česká republika Magyarország
Roche s. r. o. Roche (Magyarország) Kft.
Tel: +420 - 2 20382111 Tel: +36 -1 279 4500

Danmark Nederland
Roche Pharmaceuticals A/S Roche Nederland B.V.
Tlf: +45 - 36 39 99 99 Tel: +31 (0) 348 438000

Deutschland Norge
Roche Pharma AG Roche Norge AS
Tel: +49 (0) 7624 140 Tlf: +47 - 22 78 90 00

Eesti Österreich
Roche Eesti OÜ Roche Austria GmbH
Tel: + 372 - 6 177 380 Tel: +43 (0) 1 27739

Ελλάδα, Kύπρος Polska
Roche (Hellas) A.E. Roche Polska Sp.z o.o.
Ελλάδα Tel: +48 - 22 345 18 88
Τηλ: +30 210 61 66 100

España Portugal
Roche Farma S.A. Roche Farmacêutica Química, Lda
Tel: +34 - 91 324 81 00 Tel: +351 - 21 425 70 00

France România
Roche Roche România S.R.L.
Tél: +33 (0)1 47 61 40 00 Tel: +40 21 206 47 01

Hrvatska Slovenija
Roche d.o.o. Roche farmacevtska družba d.o.o.
Tel: + 385 1 47 22 333 Tel: +386 - 1 360 26 00

Ireland, Malta Slovenská republika
Roche Products (Ireland) Ltd. Roche Slovensko, s.r.o.
Ireland/L-Irlanda Tel: +421 - 2 52638201
Tel: +353 (0) 1 469 0700

Ísland Suomi/Finland
Roche Pharmaceuticals A/S Roche Oy
c/o Icepharma hf Puh/Tel: +358 (0) 10 554 500
Sími: +354 540 8000

Italia Sverige
Roche S.p.A. Roche AB
Tel: +39 - 039 2471 Tel: +46 (0) 8 726 1200

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

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The following information is intended exclusively for healthcare professionals:

Dosage

Gazyvaro must be administered under the close supervision of an experienced physician and in a setting with immediate and full availability of resuscitation equipment.

Tumour Lysis Syndrome (TLS) Prophylaxis and Premedication

Patients with a high tumour burden and/or high circulating lymphocyte count (> 25 x 10⁹/L) and/or impaired renal function (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatic agents (e.g. allopurinol) or an appropriate alternative treatment such as a urate oxidase (e.g. rasburicase), 12–24 hours prior to the start of Gazyvaro infusion, in accordance with current clinical practice.

All patients considered at risk should be closely monitored during the initial days of treatment, particularly regarding renal function, potassium, and uric acid levels. Any additional treatments according to guidelines, in line with current clinical practice, should be implemented. TLS is not considered a potential or identified risk in patients with NL.

Infusion-Related Reaction (IRR) Prophylaxis and Premedication

Premedication with medicinal products to reduce the risk of IRR is described in Table 1. Premedication with corticosteroids is recommended in patients with FL and is mandatory in patients with CLL during the first treatment cycle and in patients with NL (see Table 1). Premedication for subsequent infusions and other premedications should be carried out as described below.

Hypotension may occur during intravenous administration of Gazyvaro as a symptom of an IRR. Therefore, the suspension of antihypertensive treatments should be considered during the 12 hours preceding and throughout the duration of each Gazyvaro infusion, as well as during the first hour following administration.

Table 1 Premedication with medicinal products to be administered prior to Gazyvaro infusion to reduce the risk of IRR

Indication/treatment day/Cycle	Patients requiring premedication	Premedication	Administration
Cycle 1: Day 1 for CLL and FL	All patients	Intravenous corticosteroid1,4 (mandatory for CLL and recommended for FL)	To be completed at least 1 hour before Gazyvaro infusion
		Oral analgesic/antipyretic2	At least 30 minutes before Gazyvaro infusion
		Antihistamine3
Cycle 1: Day 2 for CLL only	All patients	Intravenous corticosteroid1 (mandatory)	To be completed at least 1 hour before Gazyvaro infusion
		Oral analgesic/antipyretic2
Indication/treatment day/Cycle	Patients requiring premedication	Premedication	Administration
		Antihistamine3	At least 30 minutes before Gazyvaro infusion
All subsequent infusions for CLL and FL	Patients without IRR during previous infusion	Oral analgesic/antipyretic2	At least 30 minutes before Gazyvaro infusion
	Patients with an IRR (Grade 1 or 2) during previous infusion	Oral analgesic/antipyretic2, Antihistamine3
	Patients with a Grade 3 IRR during previous infusion OR Patients with lymphocyte count >25 x 109/L prior to next treatment	Intravenous corticosteroid1,4	To be completed at least 1 hour before Gazyvaro infusion
		Oral analgesic/antipyretic2, Antihistamine3	At least 30 minutes before Gazyvaro infusion
NHL	All patients	Intravenous corticosteroid5	To be completed between 30 and 60 minutes before Gazyvaro infusion. Starting with Dose 6, intravenous corticosteroid should only be administered to patients who experienced an IRR during the previous infusion
		Oral analgesic/antipyretic6
		Antihistamine3

Dose
Chronic lymphocytic leukemia (in combination with chlorambucil)
For patients with CLL, the recommended dose of Gazyvaro in combination with chlorambucil 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 Day 1 only), and on Day 8 and Day 15 of the first 28-day treatment cycle. For infusions on Days 1 and 2, two infusion bags must be prepared (100 mg for Day 1 and 900 mg for Day 2). If the first infusion bag is administered completely without any modifications to the infusion rate and without interruptions, the second bag may be administered on the same day (without delaying the dose or repeating premedication), provided that sufficient time and appropriate conditions are available, along with adequate medical supervision throughout the entire infusion. If changes to the infusion rate are required or interruptions occur during the administration of the first 100 mg, the second bag must be administered the following 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 the 6 treatment cycles of 28 days each for patients with CLL

Cycle	Day of treatment	Gazyvaro dose
Cycle 1	Day 1	100 mg
	Day 2 (or continuation of Day 1)	900 mg
	Day 8	1 000 mg
	Day 15	1 000 mg
Cycles 2-6	Day 1	1 000 mg

Duration of treatment
Six treatment cycles, each lasting 28 days.
Follicular lymphoma
For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown
in Table 3.
Patients with previously untreated follicular lymphoma
Induction (in combination with chemotherapy)
Gazyvaro should be administered together 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 an additional 2 cycles of Gazyvaro as monotherapy, or
• Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone (CVP).

Maintenance
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 maintenance
every 2 months for 2 years or until disease progression (whichever occurs first).
Patients with follicular lymphoma refractory to or who have progressed during or within 6 months after
treatment with rituximab or a regimen containing this agent
Induction (in combination with bendamustine)
Gazyvaro should be administered for six 28-day cycles in combination with
bendamustine.
Maintenance
Patients who have achieved a complete or partial response to induction treatment with
Gazyvaro in combination with bendamustine (first 6 treatment cycles) or who have stable
disease, should continue to receive Gazyvaro 1,000 mg as monotherapy maintenance
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

Cycle	Day of treatment	Gazyvaro dose
Cycle 1	Day 1	1 000 mg
	Day 8	1 000 mg
	Day 15	1 000 mg
Cycles 2–6 or 2-8	Day 1	1 000 mg
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)	1 000 mg

Duration of treatment
Induction treatment lasting approximately six months (six cycles of Gazyvaro treatment, each cycle
lasting 28 days, in combination with bendamustine, or eight cycles of Gazyvaro treatment, each cycle
lasting 21 days, in combination with CHOP or CVP), followed by maintenance treatment every
2 months for 2 years or until disease progression (whichever occurs first).
Lupus nephritis
The recommended dose of Gazyvaro is 1,000 mg administered intravenously, according to
Table 4:
Table 4 Dose of Gazyvaro for patients with lupus nephritis

Dose number	Treatment schedule	Dose
1	Initial infusion	1 000 mg
2	Week 2 (two weeks after Dose 1)	1 000 mg
3	Week 24	1 000 mg
4	Week 26 (two weeks after Dose 3)	1 000 mg
5* and subsequent	Every 6 months	1 000 mg

Route of administration
Gazyvaro is for intravenous use and must be administered after dilution by infusion through a dedicated infusion set. Gazyvaro must not be administered as an intravenous push or bolus.
For instructions on dilution of Gazyvaro prior to administration, see below.
Guidelines for infusion rates are provided in Tables 4–9.
Chronic Lymphocytic Leukemia (CLL)
Table 5 Chronic lymphocytic leukemia: standard infusion rate in the absence of IRR/hypersensitivity in patients with CLL and recommendations if an IRR (Infusion-Related Reaction) occurs related to the previous infusion

Cycle	Day of treatment	Infusion rate The infusion rate may be increased provided the patient can tolerate it. For management of IRRs occurring during infusion, refer to the section on Management of IRRs.
Cycle 1	Day 1 (100 mg)	Administer at 25 mg/h over 4 hours. Do not increase the infusion rate.
	Day 2 (or continuation of Day 1) (900 mg)	If no IRRs occurred during the previous infusion, administer at 50 mg/h. The infusion rate may be gradually increased in increments of 50 mg/h every 30 minutes up to a maximum rate of 400 mg/h. If the patient experienced an IRR during the previous infusion, start administration at 25 mg/h. The infusion rate may be gradually increased in increments of 50 mg/h every 30 minutes up to a maximum rate of 400 mg/h.
Cycle	Day of treatment	Infusion rate The infusion rate may be increased provided the patient can tolerate it. For management of IRRs occurring during infusion, refer to the section on Management of IRRs.
	Day 8 (1,000 mg)	If no IRRs occurred during the previous infusion and the final infusion rate was 100 mg/h or faster, subsequent infusions may start at a rate of 100 mg/h, increasing in increments of 100 mg/h every 30 minutes up to a maximum rate of 400 mg/h. If the patient experienced an IRR during the previous infusion, start administration at 50 mg/h. The infusion rate may be gradually increased in increments of 50 mg/h every 30 minutes up to a maximum rate of 400 mg/h.
	Day 15 (1,000 mg)
	Cycles 2-6:	Day 1 (1,000 mg)

Follicular Lymphoma (FL)
In Cycle 1, Gazyvaro must be administered by infusion at the standard rate (see
Table 6). In patients who do not experience infusion-related reactions (IRR)
of Grade ≥ 3 during Cycle 1, Gazyvaro may be administered by short-duration infusion (approximately 90 minutes)
(short duration infusion, SDI) starting from Cycle 2 (see Table 7).
Table 6 Follicular Lymphoma: standard infusion rate and recommendations if an IRR (Infusion-Related Reaction)
related to the previous infusion occurs

Cycle	Day of treatment	Infusion rate The infusion rate may be increased provided the patient can tolerate it. For management of IRRs occurring during infusion, refer to the section on Management of IRRs.
Cycle 1	Day 1 (1,000 mg)	Administer at 50 mg/h. The infusion rate may be increased in 50 mg/h increments every 30 minutes, up to a maximum rate of 400 mg/h.
	Day 8 (1,000 mg)	If no IRRs occurred during the previous infusion or if a Grade 1 IRR occurred, and if the final infusion rate was 100 mg/h or faster, subsequent infusions may start at a rate of 100 mg/h, increasing by
	Day 15 (1,000 mg)
Cycles 2–6 or 2–8	Day 1 (1,000 mg)
Cycle	Day of treatment	Infusion rate The infusion rate may be increased provided the patient can tolerate it. For management of IRRs occurring during infusion, refer to the section on Management of IRRs.
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)	increments of 100 mg/h every 30 minutes, up to a maximum rate of 400 mg/h. If during the previous infusion the patient experienced an IRR of Grade ≥2, administer at 50 mg/h. The infusion rate may then be gradually increased in increments of 50 mg/h every 30 minutes, up to a maximum rate of 400 mg/h.

Table 7 Follicular lymphoma: short duration infusion (SDI) rates and recommendations
in case of IRR (Infusion-Related Reaction) related to the
previous infusion

Cycle	Day of treatment	Infusion rate For management of IRRs occurring during infusion, refer to the IRR Management section.
Cycles 2-6 or 2-8	Day 1 (1,000 mg)	If no Grade ≥3 IRRs occurred during Cycle 1: 100 mg/hour for 30 minutes, then 900 mg/hour for approximately 60 minutes. If a Grade 1-2 IRR with persistent symptoms until the start of the next cycle or a Grade 3 IRR occurred during the previous obinutuzumab infusion, administer the subsequent obinutuzumab infusion at the standard rate (see Table 6).
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)

Lupus nephritis (LN)
The initial infusion of Gazyvaro must be administered at the standard infusion rate for
Dose 1 (see Table 8).
Patients who do not experience infusion-related reactions of Grade ≥ 3 during the previous infusion may receive Gazyvaro via a shortened infusion (approximately 90 minutes) starting with Dose 2 (see Table 9), with continuation of premedication.
Table 8 Lupus nephritis: standard infusion rate

Dose Number	Treatment Schedule	Infusion Rate
1	Initial infusion 1,000 mg	Administer at a rate of 50 mg/h. The infusion rate may be gradually increased in 50 mg/h increments every 30 minutes up to a maximum rate of 400 mg/h. For management of IRRs occurring during infusion, refer to the IRR Management section.
2	Week 2 - two weeks after Dose 1: 1,000 mg	Administer at a rate of 100 mg/h. The infusion rate may be increased by 100 mg/h every 30 minutes up to a maximum of 400 mg/h.
3	Week 24: 1,000 mg
4	Week 26 - two weeks after Dose 3: 1,000 mg
5* and subsequent	Every 6 months: 1,000 mg

Table 9 Lupus nephritis: short-duration infusion (SDI) rates and recommendations if an
infusion-related reaction (IRR) occurred during the previous
infusion

Dose number	Infusion rate
1	See Table 8
2 and subsequent	If no Grade ≥ 3 IRR occurred during the previous infusion: 100 mg/h for 30 minutes, then 900 mg/h for approximately 60 minutes. If during the previous short infusion (SDI) a Grade 1-2 IRR with persistent symptoms or an IRR ≥ Grade 3 occurred, administer Gazyvaro infusions at the standard infusion rate (see Table 8).

Management of IRRs
Management of IRRs may require temporary interruption of administration, reduction of the infusion rate, or discontinuation of treatment with Gazyvaro as indicated below.
Chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL)

• Grade 4 (life-threatening): infusion must be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion must be temporarily suspended and symptoms treated. Infusion may be resumed upon resolution of symptoms at a reduced rate, half of the previously used rate (i.e., the rate in use when the IRR occurred); if the patient does not exhibit any symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed according to appropriate increments and intervals for the therapeutic dose (see Tables 5–7). For patients with CLL, the infusion rate on Day 1 (Cycle 1) split over the first two days may be increased to a maximum of 25 mg/h after one hour, but should not be further increased.

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

• Grade 1–2 (mild to moderate): the infusion rate must be reduced and symptoms treated. Infusion may be resumed upon resolution of symptoms; if the patient does not exhibit any symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed according to appropriate increments and intervals for the therapeutic dose (see Tables 5–7). For patients with CLL, the infusion rate on Day 1 (Cycle 1) split over the first two days may be increased to a maximum of 25 mg/h after one hour, but should not be further increased.

IRR occurring during SDI

• Grade 4 (life-threatening): infusion must be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion must be temporarily suspended and symptoms treated. Infusion may be resumed once symptoms have resolved, at a reduced rate no greater than half of the previously used rate (i.e., the rate in use when the IRR occurred) and not exceeding 400 mg/h. If the patient experiences a second Grade 3 IRR after resuming infusion, the infusion must be stopped and treatment permanently discontinued. If the patient is able to complete the infusion without further Grade 3 IRRs, the next infusion should be administered at a rate not exceeding the standard rate.
• Grade 1–2 (mild to moderate): the infusion rate must be reduced and symptoms treated. Infusion may continue upon resolution of symptoms; if the patient does not exhibit any symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed according to appropriate increments and intervals for the therapeutic dose (see Tables 5–6).

Lupus nephritis

• Grade 4 (life-threatening): infusion must be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion must be temporarily suspended and symptoms treated. Infusion may be resumed upon resolution of symptoms at a rate no higher than half of the previously used rate (i.e., the rate in use when the IRR occurred); if the patient does not exhibit further symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed based on appropriate increments and intervals for the therapeutic dose (see Tables 8 and 9). If the patient experiences a second Grade 3 IRR, infusion must be stopped and treatment permanently discontinued.
• Grade 1–2 (mild to moderate): the infusion rate must be reduced to half of the rate used at the time of the reaction and symptoms must be treated. Infusion may continue upon resolution of symptoms at the reduced rate for an additional 30 minutes. If the patient does not exhibit further symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed according to appropriate increments and intervals for the therapeutic dose (see Tables 8 and 9).

IRR occurring during SDI:

• Grade 4 (life-threatening): infusion must be stopped and treatment permanently discontinued.
• Grade 3 (severe): infusion must be temporarily suspended and symptoms treated. Infusion may be resumed after resolution of symptoms at a rate no higher than half of the previously used rate (i.e., the rate in use when the IRR occurred) and not exceeding 400 mg/h. If, after resuming infusion, the patient experiences a second Grade 3 IRR, infusion must be stopped and treatment permanently discontinued. If the patient is able to complete the infusion without further Grade 3 IRRs, the next infusion must be administered at a rate not exceeding the standard rate (see Table 8).
• Grade 1–2 (mild to moderate): the infusion rate must be reduced and symptoms treated. Infusion may continue upon resolution of symptoms; if the patient does not exhibit any symptoms indicative of an IRR, gradual escalation of the infusion rate may be resumed based on appropriate increments and intervals for the therapeutic dose (see Tables 8–9). If the patient has persistent symptoms or if a Grade 3 or higher IRR occurred during the previous 90-minute infusion, administer all subsequent Gazyvaro infusions at the standard infusion rate (see Table 8).

Instructions for dilution
Gazyvaro must be prepared by a healthcare professional using aseptic technique. Do not shake the vial. A sterile needle and syringe must be used to prepare Gazyvaro.
For CLL Cycles 2–6, FL all cycles, and throughout treatment for LN
Withdraw 40 mL of concentrate from the vial and dilute it in infusion bags made of polyvinyl chloride (PVC) or non-PVC polyolefin containing 0.9% (9 mg/mL) sodium chloride injection solution.
For CLL – Cycle 1 only
To differentiate the two infusion bags for the initial 1,000 mg dose, it is recommended to use bags of different sizes to distinguish the 100 mg dose for Day 1 of Cycle 1 from 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, dilute 4 mL in a 100 mL infusion bag made of PVC or non-PVC polyolefin, and the remaining 36 mL in a 250 mL infusion bag made of PVC or non-PVC polyolefin, each containing 0.9% (9 mg/mL) sodium chloride injection solution. Each infusion bag must be clearly labeled.
Table 10 Dilution of Gazyvaro (for CLL only)

Day of treatment	Dose of Gazyvaro to be administered	Required amount of Gazyvaro concentrate	Infusion bag size in PVC or non-PVC polyolefin
Day 1 of Cycle 1	100 mg	4 mL	100 mL
Day 1 (continued) or Day 2 of Cycle 1	900 mg	36 mL	250 mL
Starting Day 8 of Cycle 1	1,000 mg	40 mL	250 mL

In concentration ranges between 0.4 mg/mL and 20.0 mg/mL, after dilution of Gazyvaro with 0.9% (9 mg/mL) sodium chloride injection solution, no incompatibilities were observed between Gazyvaro and

• bags made of PVC, polyethylene (PE), polypropylene (PP) or polyolefins
• infusion equipment made of PVC, polyurethane (PUR) or PE
• optional in-line filters with contact surfaces made of polyethersulfone (PES), Y-sites with 3-way stopcocks made of polycarbonate (PC), and catheters made of polyether-urethane (PEU).

Other diluents, such as 5% glucose solution, must not be used.
The bag should be gently inverted to mix the solution, avoiding excessive foaming. The diluted solution must not be shaken or frozen.
Parenteral medicinal products should be inspected visually before administration to ensure there are no particles present and no change in colour.
After dilution, chemical and physical stability has been demonstrated in 0.9% (9 mg/mL) sodium chloride injection solution at concentrations of 0.4 mg/mL to 20 mg/mL for 72 hours at 2–8°C, followed by 48 hours (including infusion time) at ≤ 30°C.
From a microbiological standpoint, the prepared infusion solution should be used immediately. Otherwise, the storage times and conditions prior to administration are the responsibility of the user and must not exceed 24 hours at 2–8°C, unless the dilution was carried out under controlled and validated aseptic conditions.

Disposal
Any unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.