GAZYVARO 1000 mg Concentrate For Infusion Solution

Зміст інструкції

1. Gazyvaro 1.000 mg concentrate for solution for infusion
   1. What is Gazyvaro and what it is used for
   2. What you need to know before you are given Gazyvaro
   3. How Gazyvaro is administered
   4. Possible side effects
   5. How to store Gazyvaro
   6. Content of the pack and other information

Gazyvaro 1.000 mg concentrate for solution for infusion

obinutuzumab

Read this leaflet carefully before you use 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 any side effects occur, including those not listed in this leaflet, tell your doctor or nurse. 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 given to you
• 3. How Gazyvaro is given to you
• 4. Possible side effects
• 5. How to store Gazyvaro
• 6. Contents of the pack and other information

1. What is Gazyvaro and what it is used for

What is Gazyvaro
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 is Gazyvaro used for
Gazyvaro can be used in adults for the treatment of two different types of cancer

• Chronic Lymphocytic Leukemia(also called “CLL”)
• Gazyvaro is used in the treatment of adult patients who have not been previously treated and who have other medical conditions due to which it is unlikely that they will be able to tolerate a full dose of another medicine, used for the treatment of CLL, called fludarabine
• Gazyvaro is used in association with another anti-cancer medicine called chlorambucil
• Follicular Lymphoma(also called “FL”)
• Gazyvaro is used in patients who have not been subjected to any treatment for FL.
• Gazyvaro is used in the treatment of adult patients who have been subjected to at least one previous treatment with a medicine called rituximab and whose FL has returned or worsened during or after this treatment.
• At the beginning of the treatment of FL, Gazyvaro is used in association with other anti-cancer medicines.
• Gazyvaro can subsequently be used alone for up to 2 years as “maintenance treatment”

How Gazyvaro works

• CLL and FL are types of blood cancer that affect white blood cells called "B lymphocytes". The affected "B lymphocytes" multiply too rapidly and live too long. Gazyvaro binds to specific targets on the surface of B lymphocytes causing their death.
• When Gazyvaro is administered to patients affected by CLL and FL in association with other anti-cancer medicines in order to help slow down the worsening of the disease.

2. What you need to know before you are given Gazyvaro

Do not be given Gazyvaro if:

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

If you have any doubts, ask your doctor or nurse before you are given Gazyvaro.

Warnings and precautions
Before you are given Gazyvaro, tell your doctor or nurse if:

• you have an infection or have had an infection in the past that lasted a long time or recurred several times;
• you have taken or been given medicines that affect the immune system in the past (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 had heart problems in the past;
• you have had brain problems in the past (such as memory problems, difficulty moving or problems with sensation, vision problems);
• you have had breathing or lung problems in the past;
• you have had “hepatitis B” in the past, a type of liver disease;
• you are going to have a vaccination or you know that you might need to have one soon.

If any of these apply to you or if you are not sure, talk to your doctor or nurse before
you are given Gazyvaro.

Pay attention to the following side effects
Gazyvaro can cause some serious side effects that you need to tell your doctor or
nurse about immediately. These include:

Reactions related to the infusion

• Tell your doctor or nurse immediately if you develop any of the reactions related to the infusion listed at the beginning of section 4. Reactions related to the infusion can occur during the infusion or within 24 hours after the infusion.
• If you develop a reaction related to the infusion, you may need additional treatment, or the infusion may need to be slowed down or stopped. Once these symptoms have disappeared or improved, it may be possible to continue the infusion. The likelihood of developing these reactions is greater during the first infusion. If you develop a severe reaction related to the infusion, your doctor may decide to stop treatment with Gazyvaro.
• Before each infusion of Gazyvaro, you will be given medicines that will help to reduce the risk of possible reactions related to the infusion or “tumour lysis syndrome”. Tumour lysis syndrome is a complication that can lead to death 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, a very rare brain infection that can lead to death, has been reported with the use of Gazyvaro.
• Tell your doctor or nurse immediately if you notice you are having memory loss, difficulty speaking, difficulty walking, or loss of vision.
• If you have experienced any of these symptoms before treatment with Gazyvaro, tell your doctor immediately if you notice any changes to them, as you may need medical care.

Infections

• Tell 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 give 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
Tell your doctor or nurse if you are taking, have recently taken, or might have to take
any other medicines, including those available without a prescription and herbal medicines

Pregnancy

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

Breast-feeding

• Gazyvaro can pass into breast milk in small amounts, therefore you should not breast-feed during treatment with this medicine, and for 18 months after stopping the last treatment with Gazyvaro.

Contraception

• Use effective contraception during treatment with Gazyvaro.
• Continue to use effective 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 a reaction related to the infusion (see section 4),
do not drive, or use tools or machinery until the reaction has stopped.

3. How Gazyvaro is administered

How Gazyvaro is administered
Typically, Gazyvaro is administered under the supervision of a physician experienced in this type of
treatment. The medication is administered intravenously via infusion (intravenous infusion) over
several hours.

Treatment with Gazyvaro
Chronic Lymphocytic Leukemia

• You will receive 6 treatment cycles with Gazyvaro in association with another anti-cancer medication called chlorambucil. Each cycle lasts 28 days.
• On Day 1 of the first cycle, you will be administered the first dose of Gazyvaro of 100 milligrams (mg) via a very slow infusion. The doctor/nurse will carefully monitor you for any infusion-related reactions.
• If you do not develop any infusion-related reactions during the administration of the small portion of the first dose, the remaining portion of the first dose (900 mg) will be administered to you on the same day.
• If you should experience an infusion-related reaction, during the administration of the small portion of the first dose, the remaining portion of the first dose will be administered to you on Day 2.

The typical administration schedule is reported below.
Cycle 1 - this will include three doses of Gazyvaro over the 28 days:

• Day 1 - portion of the first dose (100 mg)
• Day 2 or Day 1 (continuation) - - remaining portion of the 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 - these will include only one dose of Gazyvaro over the 28 days:

• Day 1 - full dose (1,000 mg).

Follicular Lymphoma

• You will receive 6 or 8 treatment cycles with Gazyvaro in association with other anti-cancer medications. Each cycle lasts 28 or 21 days, depending on the other anti-cancer medications administered together with Gazyvaro.
• This induction treatment will be followed by a “maintenance phase” during which Gazyvaro will be administered to you every 2 months for up to two years until the disease progresses. Based on the state of the disease after the initial treatment cycles, the doctor will determine whether you will undergo treatment during the maintenance phase.
• The typical dosing schedule is reported below.

Induction phase
Cycle 1 - this includes three doses of Gazyvaro over 28 or 21 days, depending on the other medications
anti-cancer drugs 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 - these will include only one dose of Gazyvaro over 28 or 21 days, depending on the
other anti-cancer drugs administered together with Gazyvaro:

• Day 1- full dose (1,000 mg)

Maintenance phase

• Full dose (1,000 mg) once every 2 months for a maximum of 2 years until the disease progresses.

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

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

If you miss a Gazyvaro treatment
If you forget an appointment for administration, ask your doctor when to schedule the
next administration. In order for this medication to be fully effective, it is extremely
important to adhere to the dosage regimen.
If you have any doubts about the use of this medication, consult 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 develop any of the following symptoms
during the infusion or within 24 hours after the infusion:

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

Reported less frequently:

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

If you notice any of the above listed side effects, tell your doctor or nurse immediately.

Progressive Multifocal Leukoencephalopathy
PML, a very rare and life-threatening brain infection, has been reported with Gazyvaro.
Tell your doctor or nurse immediately if you develop:

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

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

Infections
You may be more likely to get infections during and after treatment with Gazyvaro. These infections are often simple colds, but more serious infections have also been reported. In patients who have had hepatitis B in the past, the disease has been reported to reappear and affect the liver.
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 when urinating
• feeling weak or unwell.

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

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 the nose and throat, herpes zoster
• changes in blood tests:
• anemia (low red blood cell count)
• low levels of all types of white blood cells (combined)
• low levels of neutrophils (a type of white blood cells)
• 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
• depression, anxiety
• flu
• weight gain
• runny or congested nose
• eczema
• pain in mouth or throat
• pain in the muscles and bones of the chest
• skin cancer (squamous cell carcinoma, basal cell carcinoma)
• bone pain
• irregular heartbeat (atrial fibrillation)
• problems with urination, urinary incontinence
• high blood pressure
• digestive problems (e.g., heartburn), hemorrhoids
• changes in blood tests:
• low levels of lymphocytes (a type of white blood cells), fever associated with low levels of neutrophils (a type of white blood cells)
• increased levels of potassium, phosphate or uric acid, which can cause kidney problems (part of tumor lysis syndrome)
• decreased levels of potassium
• 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 in which blood 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 above listed side effects.

Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any side effects not listed in this leaflet. You can also report side effects directly through 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 information is as follows.

• 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 pack after Exp./EXP. The expiry date refers to the last day of that month.
• Store in a refrigerator (2-8°C). Do not freeze.
• Keep the container in the outer packaging to protect it from light.

Do not dispose of any medicine in wastewater or household waste. The healthcare professional will dispose of medicines no longer in use. This will help protect the environment.

6. Content of the pack and other information

What Gazyvaro contains

• The active substance 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 injections.

Description of the appearance of Gazyvaro and contents of the pack
Gazyvaro is a concentrate for solution for infusion and is a liquid 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
D-79639 Grenzach-Wyhlen
Germany
For further information on this medicine, contact the local representative of the marketing
authorisation holder:

Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799

България
Рош България ЕООД
Тел: +359 2 818 44 44

België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11

Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)

Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111

Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 1 279 4500

Danmark
Roche a/s
Tlf: +45 - 36 39 99 99

Malta
(See Ireland)

Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140

Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050

Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380

Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00

Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100

Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739

España
Roche Farma S.A.
Tel: +34 - 91 324 81 00

Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88

France
Roche
Tél: +33 (0)1 47 61 40 00

Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00

Hrvatska
Roche d.o.o.
Tel: + 385 1 47 22 333

România
Roche România S.R.L.
Tel: +40 21 206 47 01

Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700

Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00

Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000

Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201

Italia
Roche S.p.A.
Tel: +39 - 039 2471

Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500

Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76

Sverige
Roche AB
Tel: +46 (0) 8 726 1200

Latvija
Roche Latvija SIA
Tel: +371 - 6 7039831

United Kingdom (Northern Ireland)
Roche Products (Ireland) Ltd.
Tel: +44 (0) 1707 366000

Other sources of information
More detailed information on this medicine is available on the website of the European Medicines
Agency: http://www.ema.europa.eu.
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The following information is intended exclusively for healthcare professionals:
Dosage and Administration
Gazyvaro must be administered under the close supervision of an experienced physician and in an
environment with immediate and full availability of resuscitation equipment.

Prophylaxis and premedication for tumour lysis syndrome (TLS)
Patients who present with a high tumour mass and/or a high circulating lymphocyte count
(> 25 x 10⁹/l) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and
must receive prophylaxis. Prophylaxis must consist of adequate hydration and
administration of uricostatic agents (e.g. allopurinol) or adequate alternative treatment such as
a urate oxidase (e.g. rasburicase), 12-24 hours before the start of Gazyvaro infusion according to
current clinical practice.
All patients considered at risk must be carefully monitored during the initial days of
treatment, particularly in relation to renal function, potassium and uric acid levels.
Any further treatments as per guidelines, in accordance with current clinical practice, must
be followed.

Prophylaxis and premedication for infusion-related reactions (IRR)
Premedication with medicines to be administered to reduce the risk of IRR is described in
Table 1 (see also section 4.4). Premedication with corticosteroids is recommended in
patients with LF and is mandatory in patients with CLL in the first cycle of treatment (see Table 1).
Premedication for subsequent infusions and other premedications must be carried out as
described below.
Hypotension may occur as a symptom of an IRR during intravenous administrations of Gazyvaro. Therefore, suspension of antihypertensive treatments should be considered 12 hours
before and throughout each Gazyvaro infusion, as well as in the first hour after
administration.

Table 1 Premedication with medicines to be administered before Gazyvaro infusion
to reduce the risk of IRR in patients with CLL and LF

Dose
Chronic Lymphocytic Leukaemia (in association with chlorambucil)
For patients with CLL, the recommended dose of Gazyvaro in association with chlorambucil is illustrated
in Table 2.

Cycle 1
The recommended dose of Gazyvaro in association with chlorambucil is 1,000 mg administered on
Day 1 and Day 2 (or only Day 1), and Day 8 and Day 15 of the first 28-day treatment cycle. Two
infusion bags (100 mg for Day 1 and 900 mg for Day 2) should be prepared for the infusions on Days 1 and 2. If the administration of the first bag is completed without
making changes to the infusion rate or interruptions, the
second bag can be administered on the same day (without delaying the dose or repeating the premedication), provided that there is sufficient time and conditions as well as adequate medical
monitoring throughout the entire infusion. If changes are made to the infusion rate or interruptions occur during the administration of the first 100 mg, the second bag must
be administered the next day.

Cycles 2–6
The recommended dose of Gazyvaro in association with chlorambucil is 1,000 mg administered on
Day 1 per cycle.

Table 2 Gazyvaro dose to be administered during the 6 treatment cycles lasting
28 days each for patients with CLL

Duration of treatment
Six cycles of treatment, each lasting 28 days.
Follicular Lymphoma
For patients with FL, the recommended dose of Gazyvaro in association with chemotherapy is illustrated
in Tables 3.

Patients with untreated follicular lymphoma

Induction (in association with chemotherapy)
Gazyvaro must be administered together with chemotherapy as follows:

• Six cycles lasting 28 days in association with bendamustine or
• Six cycles lasting 21 days in association with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 further cycles of Gazyvaro monotherapy or
• Eight cycles lasting 21 days in association with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone (CVP).

Maintenance
Patients who achieve complete or partial response to induction treatment with Gazyvaro in
association with chemotherapy must continue to receive Gazyvaro 1,000 mg monotherapy once every 2 months for 2 years or until disease progression (whichever occurs first).

Patients with follicular lymphoma who are unresponsive or have progressed during or

within 6 months after treatment with rituximab or a regimen containing this agent

Induction (in association with bendamustine)
Gazyvaro must be administered for six 28-day cycles in association with
bendamustine.

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

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

Duration of treatment
Induction treatment lasting approximately six months (six treatment cycles with Gazyvaro, each
lasting 28 days, in association with bendamustine, or eight treatment cycles with Gazyvaro,
each lasting 21 days, in association with CHOP or CVP), followed by maintenance every
2 months for 2 years or until disease progression (whichever occurs first).
Method of administration
Gazyvaro is for intravenous use and must be administered after dilution by infusion
through a dedicated line. Gazyvaro must not be administered as a pushor intravenous bolus.
For instructions on diluting Gazyvaro before administration see section 6.6.
Instructions on the infusion rate are shown in Tables 4-6.

Leucemia Linfocitica Cronica
Table 4 Chronic lymphocytic leukemia: standard infusion rate in the absence of
IRR/hypersensitivity in patients with CLL and recommendations if IRR occurred with the
previous infusion

Follicular Lymphoma
In Cycle 1, Gazyvaro must be administered by infusion at the standard rate (see
Table 5). In patients who do not experience infusion-related reactions (IRRs) of grade ≥ 3
during Cycle 1, Gazyvaro may be administered by short (approximately 90 minutes) duration
infusion (SDI) starting in Cycle 2 (see Table 6).

Table 5 Follicular lymphoma: standard infusion rates and recommendations if IRR occurred with
the previous infusion

Table 6 Follicular lymphoma: short duration infusion rates and recommendations if IRR occurred with
the previous infusion
Management of IRRs (all indications)
Management of IRRs may require temporary interruption of administration, reduction of
the infusion rate, or discontinuation of Gazyvaro treatment as indicated below.

• Grade 4 (potentially life-threatening): the infusion must be suspended and therapy permanently discontinued.
• Grade 3 (severe): the infusion must be temporarily suspended and symptoms must be treated. The infusion may be resumed upon resolution of symptoms, at a reduced rate of half the previously used rate (i.e., the rate used when the IRR occurred) and, if the patient shows no symptoms indicative of IRR, the gradual increase of the infusion rate may be restored based on appropriate increments and intervals for the therapeutic dose (see Tables 4-6). For patients with CLL, the infusion rate on Day 1 (Cycle 1) divided over the first two days, may be brought back to a maximum of 25 mg/h after one hour, without being further increased. If the patient experiences a grade 3 IRR for the second time, the infusion must be suspended and therapy permanently discontinued.
• Grade 1-2 (mild to moderate): the infusion rate must be reduced and symptoms must be treated. The infusion may be resumed upon resolution of symptoms and, if the patient shows no symptoms indicative of IRR, the gradual increase of the infusion rate may be restored based on appropriate increments and intervals for the therapeutic dose (see Tables 4-6). For patients with CLL, the infusion rate on Day 1 (Cycle 1) divided over the first two days, may be brought back to a maximum of 25 mg/h after one hour, without being further increased.

Management of IRRs occurring during SDI

• Grade 4 (life-threatening): the infusion must be stopped and therapy permanently discontinued.

• Grade 3 (severe): the infusion must be temporarily suspended and symptoms must be treated. The infusion may be resumed once symptoms are resolved, at a rate reduced to no more than half the previously used rate (i.e., the rate used when the IRR occurred) and no higher than 400 mg/h. If the patient experiences a second grade 3 IRR after resuming the infusion, the infusion must be stopped and therapy permanently discontinued. If the patient is able to complete the infusion without other grade 3 IRRs, the next infusion must be administered at a rate no higher than the standard rate.
• Grade 1-2 (mild to moderate): the infusion rate must be reduced and symptoms must be treated. The infusion may continue upon resolution of symptoms and, if the patient shows no symptoms indicative of an IRR, the gradual increase of the infusion rate may be restored based on appropriate increments and intervals for the therapeutic dose (see Tables 5-6).

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

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 4 mL of concentrate from the vial, 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 0.9% sodium chloride injectable solution
(9 mg/mL). Each infusion bag must be clearly labeled.
Within concentration ranges between 0.4 mg/mL and 20.0 mg/mL after dilution of
Gazyvaro with 0.9% sodium chloride injectable solution (9 mg/mL), no incompatibilities between Gazyvaro and

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

Do not use other diluents such as glucose solution (5%).
The bag should be gently inverted to mix the solution avoiding excessive foam formation. Do not shake or freeze the diluted solution.
Parenteral medicines should be visually inspected before administration to exclude the presence of particles and color change.

After dilution, physicochemical stability has been demonstrated in 0.9% sodium chloride injectable solution
(9 mg/mL) at concentrations of 0.4 mg/mL - 20 mg/mL for 24 hours at 2-8°C, followed by
48 hours (including infusion time) at ≤ 30°C.
From a microbiological point of view, the prepared infusion solution must be used
immediately. Otherwise, the storage times and conditions in use before administration are the responsibility of the user and must not exceed 24 hours at 2-8°C, unless the dilution has been carried out under controlled and validated aseptic conditions.
Disposal
Unused medicine and waste derived from such medicine must be disposed of in accordance with
local regulations.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND JUSTIFICATION FOR VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION
Scientific conclusions
Considering the assessment by the Pharmacovigilance and Risk Assessment Committee
(PRAC) of the Periodic Safety Update Reports (PSURs) for obinutuzumab, the scientific
conclusions of the PRAC are as follows:
In light of the available data on hypogammaglobulinemia from clinical studies, and considering a plausible mechanism of action, the PRAC rapporteur considers that there is at least
a reasonable possibility of a causal relationship between obinutuzumab and hypogammaglobulinemia. The
PRAC rapporteur concluded that the product information for medicinal products containing
obinutuzumab should be revised accordingly.
Having examined the PRAC recommendation, the Committee for Medicinal Products for Human Use
(CHMP) agrees with the related overall conclusions and with the justification for the recommendation.

Justification for variation of the terms of the marketing authorisation
Based on the scientific conclusions on obinutuzumab, the CHMP considers that the benefit/risk
ratio of the medicine containing obinutuzumab remains unchanged, subject to the proposed changes
to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation.